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STUDY QUESTION: Are there common mutation profiles between epithelial and stromal cells in ovarian endometriotic tissue and the normal endometrium? SUMMARY ANSWER: Our study revealed no common mutations between epithelial and stromal cells in ovarian endometriotic tissue and the normal endometrium. WHAT IS KNOWN ALREADY: Epithelial cells in both ovarian endometriotic tissue and the normal endometrium harbor somatic mutations in cancer-associated genes such as phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) and KRAS proto-oncogene, GTPase (KRAS). STUDY DESIGN, SIZE, DURATION: We performed a retrospective study to identify the mutation profiles of stromal cells in endometriotic tissue and the normal endometrium. We collected 11 endometriotic stroma samples and 10 normal endometrial stroma samples between 2013 and 2017 at a tertiary care center. PARTICIPANTS/MATERIALS, SETTING, METHODS: The laser microdissection method was used to obtain stromal cells in ovarian endometriotic and normal endometrial tissues from patients with ovarian endometriosis and/or other non-invasive gynecological diseases. Target gene sequencing was performed to assess and compare the mutation profiles of stromal cells with those of epithelial cells obtained in our previous study. For target gene sequencing, 76 genes were selected based on previous genomic analyses for ovarian endometriosis, normal endometrium, endometriosis-related ovarian cancer and endometrial cancer. MAIN RESULTS AND THE ROLE OF CHANCE: Stromal samples in ovarian endometrioma and normal endometrium harbor somatic mutations (18 mutations in 11 endometriosis samples and 16 mutations in 10 normal endometrial samples) but did not share any mutations with paired epithelial samples. The mutant allele frequency of stromal samples was significantly lower than that of epithelial samples in ovarian endometrioma (P = 6.0 × 10-11) and normal endometrium (P = 1.4 × 10-7). LIMITATIONS, REASONS FOR CAUTION: The number of genes evaluated in the mutational analysis was limited. Additionally, the functional roles of somatic mutations in stromal cells remain unclear. WIDER IMPLICATIONS OF THE FINDINGS: Different mutation profiles between paired epithelial and stromal cells in both ovarian endometrioma and normal endometrium suggest that origins of epithelial and stromal cells would be independent of each other in both normal endometrium and ovarian endometrioma; however, the theory of epithelial-mesenchymal transition is proposed in ovarian endometrioma. STUDY FUNDING/COMPETING INTEREST(S): This work was supported in part by the Japan Society for the Promotion of Science KAKENHI grant number JP15H02373 (Grant-in-Aid for Scientific Research A for I.I.), JP16H06267 (Grant-in-Aid for Young Scientists A for K.Y.), JP17K08688 (Grant-in-Aid for Scientific Research C for H.N.) and JP16H06279 (Grant-in-Aid for Scientific Research on Innovative Areas-Platforms for Advanced Technologies and Research Resources for H.N. and K.Y). There are no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: Not applicable.

DOI： 10.1093/humrep/dez155

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INTRODUCTION: BRCA gene mutations are associated with hereditary ovarian cancer. BRCA plays a key role in genome integrity, and mutations result in an increased risk for ovarian cancer. Although various guidelines recommend BRCA testing in patients with ovarian cancer, data on germline BRCA (gBRCA) mutation frequency in ovarian cancer in Japan are scarce. OBJECTIVE: This study aimed to determine gBRCA1/2 mutations in Japanese patients with ovarian cancer, stratified by clinicopathological characteristics, and to assess patients' satisfaction with pre-test genetic counseling. METHODS: The CHARLOTTE study (CHARacterizing the cross-sectionaL approach to Ovarian cancer: geneTic TEsting of BRCA; UMIN000025597) is the first large multicenter epidemiological survey of Japanese women, aged ≥20, with newly diagnosed ovarian cancer (epithelial, primary peritoneal, or fallopian tube cancer), with histologically confirmed specimens. Patients were enrolled sequentially and underwent pre-test genetic counseling for BRCA testing. Blood samples were centrally tested for the presence or absence of known gBRCA mutations. A questionnaire was used to assess patient satisfaction with pre-test genetic counseling. RESULTS: A total of 634 patients with a mean age of 56.9 years were included. Most patients (84.2%) had epithelial ovarian cancer, and 51.1% had FIGO stage III-IV cancer. Nearly all patients (99.5%) received genetic counseling before the BRCA testing, either by an obstetrician-gynecologist (42.0%) or a clinical geneticist (42.0%). The overall prevalence of gBRCA1/2 mutations was 14.7% (93/634), with gBRCA1 mutations (9.9%) more common than gBRCA2 mutations (4.7%). High-grade serous carcinoma showed a prevalence of gBRCA mutations of 28.5%. Most patients were satisfied with pre-test counseling, irrespective of the service provider's professional position. DISCUSSION: Patients with high-grade serous carcinoma and family history of ovarian cancer had a slightly higher prevalence of gBRCA mutations, but none of the subgroups had considerably high gBRCA mutation prevalence. These data suggest that gBRCA testing should be carried out in all patients with ovarian cancer.

DOI： 10.1136/ijgc-2019-000384

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Endometriosis is characterized by ectopic endometrial-like epithelium and stroma, of which molecular characteristics remain to be fully elucidated. We sequenced 107 ovarian endometriotic and 82 normal uterine endometrial epithelium samples isolated by laser microdissection. In both endometriotic and normal epithelium samples, numerous somatic mutations were identified within genes frequently mutated in endometriosis-associated ovarian cancers. KRAS is frequently mutated in endometriotic epithelium, with a higher mutant allele frequency (MAF) accompanied by arm-level allelic imbalances. Analyses of MAF, combined with multiregional sequencing, illuminated spatiotemporal evolution of the endometriosis and uterine endometrium genomes. We sequenced 109 single endometrial glands and found that each gland carried distinct cancer-associated mutations, demonstrating the heterogeneity of the genomic architecture of endometrial epithelium. Remarkable increases in MAF of mutations in cancer-associated genes in endometriotic epithelium suggest retrograde flow of endometrial cells already harboring cancer-associated mutations, with selective advantages at ectopic sites, leading to the development of endometriosis.

DOI： 10.1016/j.celrep.2018.07.037

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Nature  

We previously found that therapeutic targetable fusions are detected across various cancers. To identify therapeutic targetable fusion in uterine cervical cancer, for which no effective gene targeted therapy has yet been clinically applied, we analyzed RNA sequencing data from 306 cervical cancer samples. We detected 445 high confidence fusion transcripts and identified four samples that harbored FGFR3-TACC3 fusion as an attractive therapeutic target. The frequency of FGFR3-TACC3-fusion-positive cervical cancer is also 1.9% (2/103) in an independent cohort. Continuous expression of the FGFR3-TACC3 fusion transcript and protein induced anchorage-independent growth in the cervical epithelial cell line established from the ectocervix (Ect1/E6E7) but not in that from endocervix (End1/E6E7). Injection of FGFR3-TACC3 fusion-transfected-Ect1/E6E7 cells subcutaneously into NOG mice generated squamous cell carcinoma xenograft tumors, suggesting the association between FGFR3-TACC3 fusion and squamous cell carcinogenesis. Transfection of a FGFR3-TACC3 fusion transcript into four cervical cancer cell lines (SiHa, ME180, HeLa, and Ca Ski) induced activation of the MAPK pathway and enhancement of cell proliferation. Transcriptome analysis of the FGFR3-TACC3 fusion-transfected cell lines revealed that an IL8-triggered inflammatory response was increased, via activation of FGFR3-MAPK signaling. Continuous expression of FGFR3-TACC3 fusion led to activation of the PI3K-AKT pathway only in the two cell lines that harbored PIK3CA mutations. Sensitivity to the FGFR inhibitor, BGJ398, was found to depend on PIK3CA mutation status. Dual inhibition of both FGFR and AKT showed an obvious synergistic effect in cell lines that harbor mutant PIK3CA. Additionally, TACC3 inhibitor, KHS101, suppressed FGFR3-TACC3 fusion protein expression and showed antitumor effect against FGFR3-TACC3 fusion-transfected cell lines. FGFR3-TACC3 fusion-positive cancer has frequent genetic alterations of the PI3K/AKT pathway and selection of appropriate treatment based on PI3K/AKT pathway status should be required.

DOI： 10.1038/s41389-017-0018-2

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Oxford University Press  

DOI： 10.1093/nar/gkx1018

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Other Link： http://orcid.org/0000-0002-2254-3378

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DOI： 10.1038/onc.2014.406

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Other Link： http://orcid.org/0000-0002-2254-3378

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DOI： 10.1056/NEJMoa1402121

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Other Link： http://orcid.org/0000-0002-2254-3378

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DOI： 10.1038/ncomms3612

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Other Link： http://orcid.org/0000-0002-2254-3378

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DOI： 10.1158/1078-0432.CCR-11-2725

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Other Link： http://orcid.org/0000-0002-2254-3378

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Transcriptomic classification methods have been proposed for ovarian clear cell carcinoma. However, their clinical significance and association with pathologically evaluated tumor-infiltrating lymphocytes (TILs) remain unclear. We established two large transcriptomic datasets and analyzed RNA-sequencing data from 189 (JGOG3025-TR1 cohort) and 38 (Kyoto cohort) ovarian clear cell carcinomas. Representative histopathological slides were also digitized (102 and 38, respectively). Cell types were classified by two state-of-the-art artificial-intelligence models, and TILs were quantified. The transcriptomically defined immune subtype was associated with significantly poor prognosis (hazard ratio, 2.54; 95% CI, 1.42-4.54; p = 0.002 for OS). However, this group also contained significantly higher proportion of advanced-stage cases (p = 0.003), and multivariate analyses showed no independent prognostic effect (hazard ratio, 1.32; 95% CI, 0.68-2.58; p = 0.42 for OS). In contrast, the pathologically defined inflamed group demonstrated a trend toward improved survival, and the inflamed phenotype emerged as a statistically significant favorable prognostic factor for both OS and PFS in multivariate analyses (hazard ratio, 0.32; 95% CI, 0.13-0.78; p = 0.013 for OS. hazard ratio, 0.32; 95% CI, 0.15-0.67; p = 0.0026 for PFS). These findings indicate a discordance between transcriptome- and pathology-based immune classifications and suggest greater prognostic relevance of pathology-derived immune status.

DOI： 10.1007/s00262-026-04324-z

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Language：Japanese   Publisher：新潟産科婦人科学会  

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Language：Japanese   Publisher：東北連合産科婦人科学会・北日本産科婦人科学会  

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AIM: This study aimed to investigate maternal and perinatal outcomes in pregnancies among women aged50-54 and 55-59, to refine risk assessments and inform evidence-based counseling and perinatal management guidelines. METHODS: A nationwide registry maintained by the Japan Society of Obstetrics and Gynecology identified pregnancies between January 2013 and December 2022. Analyses included women aged 45-59 years with assisted reproductive technology pregnancies, excluding triplet or higher-order multiple gestations. Participants were categorized into three groups: 45-49, 50-54, and 55-59 years. Outcomes included cesarean section, instrumental delivery, preeclampsia, gestational diabetes mellitus, placenta previa, placenta accreta, placental abruption, postpartum hemorrhage, hysterectomy, maternal mortality, preterm birth, small for gestational age, low 5-min Apgar scores, and perinatal death. Logistic regression analyses estimated the impact of maternal age on these outcomes, adjusting for maternal baseline characteristics. RESULTS: A total of 4272 participants were included: 3877 in the 45-49 years, 350 in the 50-54 years, and 45 in the 55-59 years. Compared to the 45-49 years, women aged 50-54 had significantly higher risks of cesarean section, preeclampsia, gestational diabetes mellitus, placenta previa, placenta accreta, and preterm birth, while the instrumental delivery rate was lower. In particular, placenta previa increased significantly with advancing maternal age. However, the small sample size in the 55-59 years limited the ability to draw definitive conclusions. CONCLUSION: Women aged 50-54 years experience significantly higher risks of adverse pregnancy outcomes compared to those aged 45-49 years. The small sample size in the 55-59-year age group limits the ability to draw definitive conclusions.

DOI： 10.1111/jog.70063

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Language：Japanese   Publisher：新潟産科婦人科学会  

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IN BRIEF: By tissue-selective next-generation sequencing, we showed that adenomyotic epithelium harbored genomic alterations thought to be relevant to the development and progression of adenomyosis, including somatic mutations in several cancer-associated genes with high mutant allele frequencies and the gain of chromosome 1q. Clonal relationships among multiple adenomyotic lesions and the normal uterine endometrium delineate the oligoclonal origin of adenomyosis and the spatial expansion of mutant clones. ABSTRACT: To identify the distinctive features of mutation profiles in adenomyosis compared to the coexisting normal endometrium, multi-regional sampling was performed to collect samples of adenomyotic epithelium (n = 41), adenomyotic stroma (n = 12), and uterine endometrial epithelium (n = 53) from 21 patients with adenomyosis. To enhance the purity in this genomic study, laser microdissection was used to isolate all the samples. Target-gene sequencing and whole-exome sequencing were performed to identify somatic mutations in cancer-associated genes and the pattern of cellular expansion in adenomyosis and clonality between adenomyosis and uterine endometrium. In adenomyotic epithelium, we identified somatic mutations in cancer-associated genes such as KRAS (34.1%), PIK3CA (12.2%), ARID1A (12.1%), and FBXW7 (9.8%) with high mutant allele frequency. In uterine endometrial epithelium, frequently mutated genes included KRAS (47.2%), PIK3CA (37.8%), and ARHGAP35 (28.3%). Whole-exome sequencing revealed clonal relationships among adenomyotic lesions, and between adenomyosis and uterine endometrium. The analysis of somatic copy number alterations (SCNAs) showed recurring gain of chromosome 1q in the adenomyotic epithelium but not in the uterine endometrial endometrium. Mutational signature analysis for SNVs revealed that similar mutational processes were shared in adenomyosis and uterine endometrium. In this study, we identified multiple cancer-associated gene mutations and SCNAs relevant to the development of adenomyosis, and also clonal relationships among multiple adenomyotic lesions and normal uterine endometrium.

DOI： 10.1530/REP-25-0132

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Language：Japanese   Publisher：(一社)日本糖尿病・妊娠学会  

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Language：Japanese   Publisher：(一社)日本糖尿病・妊娠学会  

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BACKGROUND: Mesenteric lymph node (MLN) involvement is frequently observed in patients undergoing cytoreductive surgery for ovarian cancer (OC) with rectosigmoid invasion. However, MLN detection methods are not standardized, and the clinical significance of MLN involvement remains controversial. This study aimed to investigate the clinical significance of MLN involvement in patients with OC using a standardized detection method. METHODS: The study included 171 patients with stage II, III, or IV OC who underwent cytoreductive surgery. The analysis detected MLN in patients who underwent rectosigmoid resection in the same manner as for colorectal cancer: systematic regional lymph node dissection followed by systematic extraction and histopathologic examination of MLN. RESULTS: Of the 171 patients, 57 underwent rectosigmoid resection. In 56 patients (98.2 %), MLNs were detected, with a median of nine (range, 0-51) dissected nodes. Histopathologic examination confirmed MLN involvement in 30 of these 57 patients. The independent prognostic factors for progression-free survival identified by multivariate analysis were residual tumor status (P = 0.002), ascitic cytology (P = 0.034), and MLN involvement (P = 0.010). Among the 86 patients who underwent complete cytoreductive surgery, MLN involvement was significantly associated with worse prognosis (P < 0.001). However, for the 85 patients who underwent optimal or suboptimal cytoreductive surgery, MLN involvement was not a significant prognostic factor. CONCLUSIONS: In patients with OC, MLN involvement is an important prognostic factor, particularly for those undergoing complete cytoreductive surgery. Evaluation of MLNs using a standardized detection method in the same manner as for colorectal cancer may help identify patients at higher risk for a poor prognosis.

DOI： 10.1245/s10434-025-17779-8

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Language：Japanese   Publisher：新潟周産母子研究会  

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Borderline ovarian tumors primarily affect younger women and are associated with favorable prognosis, making fertility-sparing surgery a viable option. However, owing to recurrence and malignant transformation risks, careful monitoring is required. Seromucinous borderline ovarian tumors, a rare subtype that is often associated with endometriosis, lack standardized guidelines for fertility-sparing surgery or infertility management following bilateral salpingo-oophorectomy with uterine preservation. We present a case of bilateral seromucinous borderline ovarian tumors stage IC3 managed with bilateral salpingo-oophorectomy, without observed recurrence, resulting in a live birth after frozen-thawed embryo transfer using embryos preserved before surgery. This case highlights the feasibility of bilateral salpingo-oophorectomy with uterine preservation and hormone replacement therapy-assisted frozen-thawed embryo transfer for seromucinous borderline ovarian tumors, emphasizing the importance of long-term surveillance and multidisciplinary management. Further research is required to establish evidence-based guidelines for seromucinous borderline ovarian tumor treatment and infertility care post-bilateral salpingo-oophorectomy.

DOI： 10.1111/jog.16323

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Language：Japanese   Publisher：(公社)日本超音波医学会  

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Language：Japanese   Publisher：(公社)日本超音波医学会  

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OBJECTIVE: Advanced ovarian clear cell carcinoma (OCCC) is associated with poor outcomes owing to chemoresistance. Bevacizumab (Bev) is increasingly being used to treat advanced ovarian cancer; however, its efficacy in OCCC remains unclear. This study evaluated the treatment outcomes of frontline bevacizumab chemotherapy in patients with OCCC. METHODS: This retrospective multi-institutional study included patients diagnosed with advanced OCCC at eight institutions in Japan between 2008 and 2018. Patients were categorized into pre and post-market groups based on the Bev approval dates. Progression-free survival (PFS) and overall survival (OS) were analyzed using univariate and multivariate methods. Additionally, patients were classified into Bev-treated (Bev+) and non-Bev-treated (Bev-) groups, and their prognoses were compared. RESULTS: A total of 96 patients were in the pre-market group and 82 in the post-market group. The post-market group had a significantly higher proportion of patients with poor performance status and patients who underwent interval debulking surgery (p<0.01 and p<0.01, respectively). Univariate analysis demonstrated a better PFS in the post-market group (p=0.041). In multivariate analysis, better PFS (hazard ratio [HR]=0.52; p=0.002) and OS (HR=0.47; p=0.002) were observed in the post-market group than in the pre-market group. Bev+ patients had significantly better PFS and OS than Bev- patients in univariate (p<0.001 and p<0.001, respectively) and multivariate analyses (PFS: HR=0.36; p<0.001 and OS: HR=0.21; p=0.001, respectively). CONCLUSION: Incorporating Bev into frontline chemotherapy may improve outcomes in patients with advanced OCCC.

DOI： 10.3802/jgo.2025.36.e80

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Language：Japanese   Publisher：新潟産科婦人科学会  

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Cysts occurring in the presacral space may become malignant and therefore require surgical removal. A wide variety of cystic lesions can occur in the presacral space, such as tailgut cysts, dermoid cysts, and duplication cysts. However, deep endometriosis with cyst formation in the presacral space is extremely rare. Here, we report a case of deep endometriosis that presented characteristic imaging and pathological findings and required a differential diagnosis of rectal duplication cyst. A 49-year-old female was referred with a chief complaint of lower abdominal pain. Magnetic resonance imaging (MRI) revealed a cystic lesion with a three-layered wall structure on the right side of the rectum, suggesting a rectal duplication cyst. The lesion had a maximum diameter of 8 cm and extended from the lower end of the second sacral vertebra to the levator ani muscle. The cystic lesion was removed laparoscopically, and intraoperative findings revealed no communication between the cystic lesion and the rectum. We found that the wall of the deep endometriosis with cyst formation had a histopathological three-layered structure and considered that the layered structure closely resembled the intestinal wall on MRI. Deep endometriosis should be recognized as a differential diagnosis of cystic lesions in the presacral space.

DOI： 10.1007/s12328-025-02100-7

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Language：Japanese   Publisher：(公社)日本産科婦人科学会  

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Language：Japanese   Publisher：(公社)日本産科婦人科学会  

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Language：Japanese   Publisher：(公社)日本産科婦人科学会  

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Language：Japanese   Publisher：新潟医学会  

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Publishing type：Research paper (scientific journal)   Publisher：XMLink  

DOI： 10.3802/jgo.2025.36.e57

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Other Link： https://ejgo.org/DOIx.php?id=10.3802/jgo.2025.36.e57

Publisher：診断と治療社  

DOI： 10.34433/og.0000000958

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Objective This study aimed to investigate whether the amount of blood loss during delivery in patients with low-lying placenta is affected by the planned mode of delivery, internal os distance, and warning bleeding. Materials and methods We conducted a single-center retrospective study encompassing women with singleton pregnancies diagnosed with low-lying placenta between January 2012 and December 2021. Data for maternal demographic details and pregnancy outcomes were extracted from the institution's records. We analyzed blood loss during delivery according to the planned delivery mode, internal os distance (≥10 mm or within 10 mm), and the occurrence of warning bleeding. We also assessed the frequency of abnormal hemorrhage at delivery. Statistical analyses included the Mann-Whitney U test and Fisher's exact probability test, with significance set at p<0.05. Results This study included 27 pregnant women. The planned delivery mode and internal os distance showed no statistically significant impact on the amount of blood loss or frequency of abnormal hemorrhage at delivery. However, the occurrence of warning bleeding had a significant effect on both factors. Conclusion In patients diagnosed with a low-lying placenta with warning bleeding, cautious delivery management is recommended owing to the possible increased risk of abnormal hemorrhage at delivery.

DOI： 10.7759/cureus.74858

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BACKGROUND: Considerable interobserver variability exists in diagnosis of ovarian high-grade endometrioid carcinoma (HGEC) and high-grade serous carcinoma (HGSC) due to histopathological similarities. While homologous recombination deficiency (HRD) correlates with drug sensitivity in HGSC, the molecular features of HGEC are unclear. METHODS: Fresh-frozen samples from 15 ovarian HGECs and 274 ovarian HGSCs in the JGOG-TR2 cohort were submitted to targeted DNA sequencing, RNA sequencing, DNA methylation array, and SNP array. We additionally analyzed 555 ovarian HGSCs from TCGA-OV and 287 endometrial high-grade carcinomas from TCGA-UCEC. RESULTS: Unsupervised clustering using copy number signatures identified four distinct tumor groups (C1, C2, C3 and C4). C1 (n = 41) showed CCNE1 amplification and poor survival. C2 (n = 160) and C3 (n = 59) showed high BRCA1/2 alteration frequency with low and moderate ploidy, respectively. C4 (n = 22) was characterized by favorable outcome, higher HGEC proportion, no BRCA1/2 alteration or CCNE1 amplification, and low levels of HRD score, ploidy, intra-tumoral heterogeneity, cell proliferation rate, and WT1 gene expression. Notably, C4 exhibited a normal endometrium-like DNA methylation profile, thus, defined as "HGEC-type" tumors, which were also identified in TCGA-OV and TCGA-UCEC. CONCLUSIONS: Ovarian "HGEC-type" tumors present a non-HRD status, favorable prognosis, and endometrial differentiation, possibly constituting a subset of clinically diagnosed HGSCs.

DOI： 10.1038/s41416-024-02837-x

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Schwannomas consist of both high-cellularity regions (Antoni A area) and hypocellular regions (Antoni B area) in histopathological findings. Neurofibromas characteristically consist of CD34 positive spindle cells with thin, wavy, nuclei and wavy collagen bands. Previous reports have described segments of schwannomas with neurofibroma features as hybrid tumors, although hybrid tumors were diagnosed based on partial CD34 positivity in many previous reports. On the other hand, the Antoni B area of some schwannomas was reported to be positive for CD34. Therefore, the definition of a hybrid tumor has not been clear. The objective of this study was to determine whether only CD34 positive findings in schwannomas could be used to define a hybrid tumor. In the analysis of our patient with schwannomatosis caused by a novel LZTR1 germline mutation, part of the tumor had CD34 positive hypocellular regions. These regions contained no thin, wavy, nuclei, indicating an Antoni B area. Laser microdissection was used to investigate the genetic background and differences in molecular mechanisms between CD34 positive and CD34 negative regions. All mutations identified in CD34 positive regions were also found in CD34 negative regions. Our data could not clear the genetic background of Antoni B which was CD34 positive area. We then reviewed the pathologies of 66 sporadic schwannomas. Histopathological examinations of all schwannomas revealed the absence of thin, wavy, nuclei and wavy collagen bands, and no hybrid tumors were found in any of the cases. Ten of 66 patients were randomly selected for CD34 immunostaining and positivity was found in all cases. Our data suggest that it is difficult to distinguish schwannomas by staining for CD34 alone, as Antoni B areas can also be positive for CD34. Therefore, CD34 staining alone should not be used to diagnose hybrid tumors in patients with schwannomas.

DOI： 10.1111/1346-8138.17343

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Cancer stem cells are associated with aggressive phenotypes of malignant tumors. A prominent feature of uterine endometrial cancer is the activation of the PI3K-Akt-mTOR pathway. In this study, we present variations in sensitivities to a PI3K-Akt-mTORC1 inhibitor among in vitro endometrial cancer stem cell-enriched spheroid cells from clinical specimens. The in vitro sensitivity was consistent with the effects observed in in vivo spheroid-derived xenograft tumor models. Our findings revealed a complementary suppressive effect on endometrial cancer spheroid cell growth with the combined use of aldehyde dehydrogenase (ALDH) and PI3K-Akt inhibitors. In the PI3K-Akt-mTORC1 signaling cascade, the influence of ALDH on mTORC1 was partially channeled through retinoic acid-induced lactate dehydrogenase A (LDHA) activation. LDHA inhibition was found to reduce endometrial cancer cell growth, aligning with the effects of mTORC1 inhibition. Building upon our previous findings highlighting ALDH-driven glycolysis through GLUT1 in uterine endometrial cancer spheroid cells, curbing mTORC1 enhanced glucose transport via GLUT1 activation. Notably, elevated LDHA expression correlated with adverse clinical survival and escalated tumor grade, especially in advanced stages. Collectively, our findings emphasize the pivotal role of ALDH-LDHA-mTORC1 cascade in the proliferation of endometrial cancer. Targeting the interaction between mTORC1 and ALDH-influenced glycolysis holds promise for developing novel strategies to combat this aggressive cancer.

DOI： 10.1038/s41420-024-02204-y

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Language：English   Publisher：(一社)日本癌治療学会  

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AIM: To analyze temporal trends and regional variations in operative vaginal delivery (OVD) in Japan. METHODS: Using the National Database of Health Insurance Claims and Specific Health Checkups of Japan from 2014 to 2021, we identified the numbers of vacuum and forceps deliveries. We analyzed annual totals and proportions of OVDs and calculated the mean age of women undergoing these deliveries. We also predicted trends in OVD for the next 20 years and compared geographical differences in the proportions of forceps deliveries among OVDs. RESULTS: During the observation period, out of 7 368 814 total births, 8.4% were through OVD, including 7.6% by vacuum and 0.8% by forceps. Both delivery methods showed an increasing trend from 2014 to 2021: vacuum deliveries rose from 7.0% to 8.7%, and forceps deliveries increased from 0.6% to 1.0%. Notably, the proportion of forceps deliveries in OVD increased from 8.1% to 10.5%. The mean age was higher for forceps deliveries than vacuum deliveries. According to our predictions, vacuum deliveries may continue to increase, but forceps deliveries may stabilize. The proportion of forceps deliveries among OVDs ranged from 0% to 38% across Japanese prefectures. CONCLUSIONS: This study shows an increase in the use of OVD in Japan from 2014 to 2021. There are large regional differences in the choice between vacuum and forceps deliveries. These findings can help us understand the practice of OVD in Japan.

DOI： 10.1111/jog.16039

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Uterine rupture can heal naturally without the need for surgical intervention. However, reports on subsequent pregnancies are limited. A 27-year-old woman, gravida 2, para 1, visited our institution at seven weeks of gestation. She had previously experienced uterine rupture with postpartum hemorrhage, which had healed naturally without surgical intervention. We thoroughly explained the perinatal complications associated with the subsequent pregnancy, particularly the risk of uterine rupture recurrence, and managed her pregnancy progress carefully. We took great care to ensure that signs of a silent rupture were not missed on imaging examinations. A planned cesarean delivery was performed at 35 weeks of gestation, resulting in an uneventful pregnancy outcome. We report the details of our management of a subsequent pregnancy in a woman who had previously experienced uterine rupture with natural healing. Our findings may serve to support healthcare providers managing similar cases.

DOI： 10.7759/cureus.70322

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Publishing type：Research paper (scientific journal)  

DOI： 10.1016/S1470-2045(24)00334-6

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Language：Japanese   Publisher：新潟産科婦人科学会  

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Language：Japanese   Publisher：(一社)日本糖尿病・妊娠学会  

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Language：Japanese   Publisher：(一社)日本糖尿病・妊娠学会  

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OBJECTIVE: This study aimed to determine whether the number of resected pelvic lymph nodes (PLNs) affects the prognosis of endometrial cancer (EC) patients at post-operative risk of recurrence. METHODS: JGOG2043 was a randomized controlled trial to assess the efficacy of three chemotherapeutic regimens as adjuvant therapy in EC patients with post-operative recurrent risk. A retrospective analysis was conducted on 250 patients who underwent pelvic lymphadenectomy alone in JGOG2043. The number of resected and positive nodes and other clinicopathologic risk factors for survival were retrieved. RESULTS: There were 83 patients in the group with less than 20 PLNs removed (group A), while 167 patients had 20 or more PLNs removed (group B). There was no significant difference in patients' backgrounds between the two groups, and the rate of lymph node metastasis was not significantly different. There was a trend toward fewer pelvic recurrences in group B compared with group A (3.5% vs. 9.6%; p=0.050). Although Kaplan-Meier analysis showed no statistically significant difference in survival rates between the two groups (5-year overall survival [OS]=90.3% vs. 84.3%; p=0.199), multivariate analysis revealed that resection of 20 or more nodes is one of the independent prognostic factors (hazard ratio=0.49; 95% confidence interval=0.24-0.99; p=0.048), as well as surgical stage, high-risk histology, and advanced age for OS. CONCLUSION: Resection of 20 or more PLNs was associated with improved pelvic control and better survival outcomes in EC patients at risk of recurrence who underwent pelvic lymphadenectomy alone and were treated with adjuvant chemotherapy.

DOI： 10.3802/jgo.2025.36.e3

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Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVE: This study aimed to show the results of radical radiation therapy (RT) and concurrent chemoradiotherapy (CCRT) for vulvar cancer (VC) based on data from a Japanese nationwide survey. MATERIALS AND METHODS: We collected data from 108 institutions on cases of VC diagnosed between January 2001 and December 2010. Patients with histologically proven squamous cell carcinoma and adenocarcinoma with curative intent were selected, and 172 patients with VC were included in this study. The collected data were analyzed for overall survival (OS) using the Kaplan-Meier method. Univariate and multivariate analyses were performed to examine the prognostic factors for patients with VC. RESULTS: The median follow-up period was 16.8 (range; 3.2-154.8) months. Fifty-five patients received CCRT, and 117 patients received RT alone. The 2-year OS rates (95% confidence interval [CI]) for stages I, II, III, and IV were 77.9% (55.8-100.0), 71.9% (53.8-89.9), 55.4% (42.5-68.3), and 41.5% (27.3-55.7) respectively. Univariate analyses showed that the FIGO stage (p = 0.001), tumor diameter (p = 0.005), and lymph node (LN) status (p = 0.001) were associated with OS. The concurrent use of chemotherapy resulted in a significantly longer OS in Stage III (p = 0.013). Multivariate analysis showed that the hazard ratios (95% CI) for tumor diameter, positivity for LN metastasis, and RT alone (no concurrent chemotherapy) were 1.502 (1.116-2.021), 1.801 (1.287-2.521), and 1.936 (1.187-3.159), respectively. CONCLUSIONS: Our analysis revealed that CCRT should be recommended, especially for Stage III VC patients. Further studies are warranted to determine who benefits from CCRT, considering primary tumor size and LN status. The study was registered at the University Hospital Medical Information Network (protocol number: UMIN000017080) on April 8th, 2015.

DOI： 10.1007/s11604-024-01557-9

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Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.xcrm.2024.101532

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1007/s10396-023-01404-w

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Publishing type：Research paper (scientific journal)   Publisher：Wiley  

Abstract

Lynch syndrome‐associated endometrial cancer patients often present multiple synchronous tumors and this assessment can affect treatment strategies. We present a case of a 27‐year‐old woman with tumors in the uterine corpus, cervix, and ovaries who was diagnosed with endometrial cancer and exhibited cervical invasion and ovarian metastasis. Her family history suggested Lynch syndrome, and genetic testing identified a variant of uncertain significance, MLH1 p.L582H. We conducted immunohistochemical staining, microsatellite instability analysis, and Sanger sequencing for Lynch syndrome‐associated cancers in three generations of the family and identified consistent MLH1 loss. Whole‐exome sequencing for the corpus, cervical, and ovarian tumors of the proband identified a copy‐neutral loss of heterozygosity (LOH) occurring at the MLH1 position in all tumors. This indicated that the germline variant and the copy‐neutral LOH led to biallelic loss of MLH1 and was the cause of cancer initiation. All tumors shared a portion of somatic mutations with high mutant allele frequencies, suggesting a common clonal origin. There were no mutations shared only between the cervix and ovary samples. The profiles of mutant allele frequencies shared between the corpus and cervix or ovary indicated that two different subclones originating from the corpus independently metastasized to the cervix or ovary. Additionally, all tumors presented unique mutations in endometrial cancer‐associated genes such as ARID1A and PIK3CA. In conclusion, we demonstrated clonal origin and genomic diversity in a Lynch syndrome‐associated endometrial cancer, suggesting the importance of evaluating multiple sites in Lynch syndrome patients with synchronous tumors.

DOI： 10.1002/gcc.23231

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Language：Japanese   Publisher：新潟産科婦人科学会  

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Language：Japanese   Publisher：(公社)日本産科婦人科学会  

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Publishing type：Research paper (scientific journal)   Publisher：MDPI AG  

Endometriosis is known to be associated with an increased risk of endometrioid and clear cell ovarian cancer. However, the association between endometriosis and endometrial cancer is controversial. Therefore, we retrospectively analyzed the medical records of women with endometrial cancer who had undergone surgery at our institution to evaluate the clinicopathological relationship between endometrial cancer and endometriosis. The study included 720 women pathologically diagnosed with endometrial cancer at our hospital between 2000 and 2020. The participants were allocated to two groups of patients with endometrial cancer: patients with endometriosis (n = 101) and patients without endometriosis (n = 619). Endometrial cancer patients with endometriosis were significantly younger (median age 54.0 vs. 58.0; p = 0.002). In addition, endometrial cancer patients with endometriosis had fewer pregnancies and deliveries (median pregnancy 1.58 vs. 1.99; p = 0.019, median delivery 1.25 vs. 1.56; p = 0.012). The percentage of patients classified as stage IA was significantly higher in those with endometrial cancer with endometriosis (68.3% vs. 56.4%; p = 0.029). In the analysis of synchronous ovarian cancer, the percentage of dual primary cancer was higher in patients with endometriosis (14.9% vs. 1.6%; p &lt; 0.001). The association of young-onset early-stage endometrial cancer with endometriosis is an important finding that cannot be ignored clinically.

DOI： 10.3390/cancers15235635

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OBJECTIVE: We aimed to quantify the incidence of recurrent uterine rupture in pregnant women. DATA SOURCES: A literature search of PubMed, Web of Science, Cochrane Central, and ClinicalTrials.gov for observational studies was performed from 2000 to 2023. METHODS OF STUDY SELECTION: Of the 7,440 articles screened, 13 studies were included in the final review. We included studies of previous uterine ruptures that were complete uterine ruptures , defined as destruction of all uterine layers, including the serosa. The primary outcome was the pooled incidence of recurrent uterine rupture. Between-study heterogeneity was assessed with the I2 value. Subgroup analyses were conducted in terms of the country development status, year of publication, and study size (single center vs national study). The secondary outcomes comprised the following: 1) mean gestational age at which recurrent rupture occurred, 2) mean gestational age at which delivery occurred without recurrent rupture, and 3) perinatal complications (blood loss, transfusion, maternal mortality, and neonatal mortality). TABULATION, INTEGRATION, AND RESULTS: A random-effects model was used to pool the incidence or mean value and the corresponding 95% CI with R software. The pooled incidence of recurrent uterine rupture was 10% (95% CI 6-17%). Developed countries had a significantly lower uterine rupture recurrence rate than less developed countries (6% vs 15%, P =.04). Year of publication and study size were not significantly associated with recurrent uterine rupture. The mean number of gestational weeks at the time of recurrent uterine rupture was 32.49 (95% CI 29.90-35.08). The mean number of gestational weeks at the time of delivery without recurrent uterine rupture was 35.77 (95% CI 34.95-36.60). The maternal mortality rate was 5% (95% CI 2-11%), and the neonatal mortality rate was 5% (95% CI 3-10%). Morbidity from hemorrhage, such as bleeding and transfusion, was not reported in any study and could not be evaluated. CONCLUSION: This systematic review estimated a 10% incidence of recurrent uterine rupture. This finding will enable appropriate risk counseling in patients with prior uterine rupture. SYSTEMATIC REVIEW REGISTRATION: PROSPERO, CRD42023395010.

DOI： 10.1097/AOG.0000000000005418

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Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVE: To compare maternal outcomes of prenatally- and non-prenatally-diagnosed placenta accreta spectrum (PAS). DATA SOURCES: A systematic literature search was performed in PubMed, the Cochrane database, and Web of Science until 28 November 2022. STUDY ELIGIBILITY CRITERIA: Studies comparing the clinical presentation of prenatally- and non-prenatally-diagnosed PAS were included. Primary outcomes were emergent cesarean delivery, hysterectomy, blood loss volume, number of transfused blood product units, urological injury, coagulopathy, reoperation, intensive care unit admission, and maternal death. We also calculated the pooled mean values for blood loss volume and the number of transfused blood product units. Secondary outcomes comprised maternal age, gestational age at birth, nulliparity, prior cesarean delivery, prior uterine procedure, assisted reproductive technology, placenta increta/percreta, and placenta previa. STUDY APPRAISAL AND SYNTHESIS METHODS: Study screening was conducted after duplicates were identified and removed. The quality of each study and the publication bias were assessed. Forest plots and I2 statistics were calculated for each study outcome for each group. The main analysis was a random-effects analysis. RESULTS: 415 abstracts and 157 full-text studies were evaluated. Thirty-one studies were analyzed. Prenatally-diagnosed PAS was associated with a significantly lower rate of emergency cesarean delivery (odds ratio (OR), 0.37; 95% CI, 0.21-0.67), higher hysterectomy rate (OR, 1.98; 95% CI, 1.02-3.83), lower blood loss volume (mean difference, -0.65; 95% CI, -1.17 to -0.13), and lower number of transfused red blood cell units (mean difference, -1.96; 95% CI, -3.25 to -0.68) compared with non-prenatally-diagnosed PAS. Pooled mean values for blood loss volume and the number of transfused blood product units tended to be lower in the prenatally- vs non-prenatally-diagnosed PAS groups. Nulliparity (OR, 0.14; 95% CI, 0.10-0.20), prior cesarean delivery (OR, 6.81; 95% CI, 4.12-11.25), assisted reproductive technology (OR, 0.19; 95% CI, 0.06-0.61), placenta increta/percreta (OR, 3.97; 95% CI, 2.24- 7.03), and placenta previa (OR, 6.81; 95% CI, 4.12-11.25) showed statistical significance. No significance differences were found for the other outcomes. CONCLUSIONS: Despite its severity, the positive impact of prenatally-diagnosed PAS on outcomes underscores the necessity of a prenatal diagnosis. Additionally, the pooled mean values provide a preoperative preparation guideline.

DOI： 10.1016/j.ajogmf.2023.101197

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Language：English   Publishing type：Research paper (scientific journal)  

BRCA1/2 mutations are robust biomarkers for platinum-based chemotherapy in epithelial ovarian cancers. However, BRCA1/2 mutations in clear cell ovarian carcinoma (CCC) are less frequent compared to high-grade serous ovarian cancer (HGSC). The discovery of biomarkers that can be applied to CCC is an unmet need in chemotherapy. Schlafen 11 (SLFN11) has attracted attention as a novel sensitizer for DNA-damaging agents including platinum. In this study, we investigated the utility of SLFN11 in HGSC and CCC for platinum-based chemotherapy. SLFN11 expression was analyzed retrospectively by immunohistochemistry across 326 ovarian cancer samples. The clinicopathologic significance of SLFN11 expression was analyzed across 57 advanced HGSC as a discovery set, 96 advanced HGSC as a validation set, and 57 advanced CCC cases, all of whom received platinum-based chemotherapy. BRCA1/2 mutation was analyzed using targeted-gene sequencing. In the HGSC cohort, the SLFN11-positive and BRCA mutation group showed significantly longer while the SLFN11-negative and BRCA wild-type group showed significantly shorter progression-free survival and overall survival. Moreover, SLFN11-positive HGSC shrunk significantly better than SLFN11-negative HGSC after neoadjuvant chemotherapy. Comparable results were obtained with CCC but without consideration of BRCA1/2 mutation due to a small population. Multivariate analysis identified SLFN11 as an independent factor for better survival in HGSC and CCC. The SLFN11-dependent sensitivity to platinum and PARP inhibitors were validated with genetically modified non-HGSC ovarian cancer cell lines. Our study reveals that SLFN11 predicts platinum sensitivity in HGSC and CCC independently of BRCA1/2 mutation status, indicating that SLFN11 assessment can guide treatment selection in HGSC and CCC.

DOI： 10.1158/1535-7163.MCT-23-0257

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Language：Japanese   Publisher：東北連合産科婦人科学会・北日本産科婦人科学会  

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Language：Japanese   Publisher：新潟医学会  

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2023&ichushi_jid=J00990&link_issn=&doc_id=20240730160002&doc_link_id=%2Fdg3nigta%2F2023%2F013708%2F002%2F0263-0273%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fdg3nigta%2F2023%2F013708%2F002%2F0263-0273%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：Japanese   Publisher：新潟産科婦人科学会  

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Language：Japanese   Publisher：新潟周産母子研究会  

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Language：English   Publishing type：Research paper (scientific journal)  

IMPORTANCE: Randomized clinical trials examining the effectiveness of neoadjuvant chemotherapy (NACT) for advanced ovarian cancer predominantly included patients with high-grade serous carcinomas. The use and outcomes of NACT in less common epithelial carcinomas are understudied. OBJECTIVE: To investigate the uptake and survival outcomes in treatment with NACT for less common histologic subtypes of epithelial ovarian cancer. DESIGN, SETTING, AND PARTICIPANTS: A retrospective cohort study and systematic literature review with meta-analysis was conducted using the National Cancer Database from 2006 to 2017 and the National Cancer Institute's Surveillance, Epidemiology, and End Results Program from 2006 to 2019. Data analysis was performed from July 2022 to April 2023. The evaluation included patients with stage III to IV ovarian cancer with clear cell, mucinous, or low-grade serous histologic subtypes who received multimodal treatment with surgery and chemotherapy. EXPOSURES: Exposure assignment per the sequence of treatment: primary debulking surgery (PDS) followed by chemotherapy (PDS group) or NACT followed by interval surgery (NACT group). MAIN OUTCOMES AND MEASURES: Temporal trends and characteristics of NACT use were assessed using multivariable analysis, and overall survival (OS) was assessed with the inverse probability of treatment weighting propensity score. RESULTS: A total of 3880 patients were examined in the National Cancer Database including 1829 women (median age, 56 [IQR, 49-63] years) with clear cell, 1156 women (median age, 53 [IQR, 42-64] years) with low-grade serous, and 895 women (median age, 57 [IQR, 48-66] years) with mucinous carcinomas. NACT use increased in patients with clear cell (from 10.2% to 16.2%, 58.8% relative increase; P < .001 for trend) or low-grade serous (from 7.7% to 14.2%, 84.4% relative increase; P = .007 for trend) carcinoma during the study period. This association remained consistent in multivariable analysis. NACT use also increased, but nonsignificantly, in mucinous carcinomas (from 8.6% to 13.9%, 61.6% relative increase; P = .07 for trend). Across the 3 histologic subtypes, older age and stage IV disease were independently associated with NACT use. In a propensity score-weighted model, the NACT and PDS groups had comparable OS for clear cell (4-year rates, 31.4% vs 37.7%; hazard ratio [HR], 1.12; 95% CI, 0.95-1.33) and mucinous (27.0% vs 26.7%; HR, 0.90; 95% CI, 0.68-1.19) carcinomas. For patients with low-grade serous carcinoma, NACT was associated with decreased OS compared with PDS (4-year rates, 56.4% vs 81.0%; HR, 2.12; 95% CI, 1.55-2.90). Increasing NACT use and histologic subtype-specific survival association were also found in the Surveillance, Epidemiology, and End Results Program cohort (n = 1447). A meta-analysis of 4 studies, including the current study, observed similar OS associations for clear cell (HR, 1.13; 95% CI, 0.96-1.34; 2 studies), mucinous (HR, 0.93; 95% CI, 0.71-1.21; 2 studies), and low-grade serous (HR, 2.11; 95% CI, 1.63-2.74; 3 studies) carcinomas. CONCLUSIONS AND RELEVANCE: Despite the lack of data on outcomes of NACT among patients with less common carcinomas, this study noted that NACT use for advanced disease has gradually increased in the US. Primary chemotherapy for advanced-stage, low-grade serous ovarian cancer may be associated with worse survival compared with PDS.

DOI： 10.1001/jamanetworkopen.2023.18602

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Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVE: We aimed to conduct a systematic review and meta-analysis to assess clinical characteristics related to pathologically proven placenta accreta spectrum (PAS) without placenta previa. DATA SOURCES: A literature search of PubMed, the Cochrane database, and Web of Science was performed from inception to September 7, 2022. STUDY ELIGIBILITY CRITERIA: The primary outcomes were invasive placenta (including increta or percreta), blood loss, hysterectomy, and antenatal diagnosis. Additionally, maternal age, assisted reproductive technology, previous cesarean section, and previous uterine procedures were investigated as potential risk factors. The inclusion criteria were studies evaluating the clinical presentation of pathologically diagnosed PAS without placenta previa. STUDY APPRAISAL AND SYNTHESIS METHODS: Study screening was conducted after duplicates were identified and removed. The quality of each study and the publication bias were assessed. Forest plots and I2 statistics were calculated for each study outcome for each group. The main analysis was a random-effects analysis. RESULTS: Among 2598 studies that were initially retrieved, five were included in the review. With the exception of one study, four studies could be included in the meta-analysis. This meta-analysis showed that PAS without placenta previa was associated with a less risk of invasive placenta (OR, 0.24; 95% CI, 0.16-0.37), blood loss (MD, -1.19; 95% CI, -2.09 to -0.28) and hysterectomy (OR, 0.11; 95% CI, 0.02-0.53), and more difficult to diagnose prenatally (OR, 0.13; 95% CI, 0.04-0.45) than PAS with placenta previa. Additionally, assisted reproductive technology and a previous uterine procedure were strong risk factors for PAS without placenta previa, while previous cesarean section was a strong risk factor for PAS with placenta previa. CONCLUSIONS: The differences in clinical aspects of PAS with and without placenta previa need to be understood.

DOI： 10.1016/j.ajogmf.2023.101027

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Language：English   Publishing type：Research paper (scientific journal)  

The development of new treatments for gynecological malignancies has been conducted mainly through collaborative international phase III trials led by the United States and Europe. The survival outcomes of many gynecological malignancies have greatly improved as a result. Recent large-scale genome-wide association studies have revealed that drug efficacy and adverse event profiles are not always uniform. Thus, it is important to validate new treatment options in each country to safely and efficiently provide newly developed treatment options to patients with gynecological malignancies. The Japanese Gynecologic Oncology Group (JGOG) is conducting 5 cohort studies (JGOG 3026, 3027, 3028, 3030, and 3031) to establish real-world data (RWD) of poly(ADP-ribose) polymerase (PARP) inhibitor use in patients with advanced or recurrent epithelial ovarian cancer. The RWD constructed will be used to provide newly developed PARP inhibitors for women with advanced or recurrent ovarian cancer in a safer and more efficient manner as well as to develop further treatment options. In 2022, The JGOG, Korean Gynecologic Oncology Group, Chinese Gynecologic Cancer Society, and Taiwanese Gynecologic Oncology Group established the East Asian Gynecologic Oncology Trial Group to collaborate with East Asian countries in clinical research on gynecologic malignancies and disseminate new knowledge on gynecologic malignancies from Asia. The JGOG will conduct a collaborative integrated analysis of the RWD generated from Asian countries and disseminate real-world clinical knowledge regarding new treatment options that have been clinically implemented.

DOI： 10.3802/jgo.2023.34.e62

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Although the gross and microscopic features of squamous cell carcinoma arising from ovarian mature cystic teratoma (MCT-SCC) vary from case to case, the spatial spreading of genomic alterations within the tumor remains unclear. To clarify the spatial genomic diversity in MCT-SCCs, we performed whole-exome sequencing by collecting 16 samples from histologically different parts of two MCT-SCCs. Both cases showed histological diversity within the tumors (case 1: nonkeratinizing and keratinizing SCC and case 2: nonkeratinizing SCC and anaplastic carcinoma) and had different somatic mutation profiles by histological findings. Mutation signature analysis revealed a significantly enriched apolipoprotein B mRNA editing enzyme catalytic subunit (APOBEC) signature at all sites. Intriguingly, the spread of genomic alterations within the tumor and the clonal evolution patterns from nonmalignant epithelium to cancer sites differed between cases. TP53 mutation and copy number alterations were widespread at all sites, including the nonmalignant epithelium, in case 1. Keratinizing and nonkeratinizing SCCs were differentiated by the occurrence of unique somatic mutations from a common ancestral clone. In contrast, the nonmalignant epithelium showed almost no somatic mutations in case 2. TP53 mutation and the copy number alteration similarities were observed only in nonkeratinizing SCC samples. Nonkeratinizing SCC and anaplastic carcinoma shared almost no somatic mutations, suggesting that each locally and independently arose in the MCT. We demonstrated that two MCT-SCCs with different histologic findings were highly heterogeneous tumors with clearly different clones associated with APOBEC-mediated mutagenesis, suggesting the importance of evaluating intratumor histological and genetic heterogeneity among multiple sites of MCT-SCC.

DOI： 10.1111/cas.15754

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Language：English   Publishing type：Research paper (scientific journal)  

AIM: In this review, We compared clinical characteristics of pregnant women aged 50 and older with those aged 45-49. Pregnant women ≥45 years are strongly associated with pregnancy-related complications, such as cesarean section rate, gestational hypertension, gestational diabetes mellitus, and preterm birth. Although pregnant women ≥50 years are considered more high-risk, differences in pregnancy outcomes between those over 45 and 50 years of age are unclear. METHODS: Our source strategy included using PubMed, the Cochrane Central Register of Controlled Trials, and Web of Science databases to include studies published between January 1, 2010 and September 30, 2022. The study population was pregnant women 50 years and older; the control group was pregnant women aged 45-49 years. Primary outcomes were cesarean section, gestational hypertension, gestational diabetes mellitus, and preterm birth. The secondary outcomes were small-for-gestational age, 5-min Apgar score < 7, neonatal intensive care unit admission (as neonatal outcomes), nulliparity, assisted reproductive technology (ART), and multifetal pregnancy (as maternal backgrounds). RESULTS: The incidence of cesarean section, gestational hypertension, and preterm delivery was significantly higher in those 50 years and older; however, significant differences disappeared when pooled analyses were limited to singleton pregnancies. ART was significantly more likely to be used for conception of pregnant women ≥50 years. Infants of women ≥50 years were more likely to be admitted to NICUs. CONCLUSIONS: The differences in outcomes between the two groups are obviously influenced by multiple pregnancies, therefore, reproductive medicine specialists should aim for singleton pregnancies in ART.

DOI： 10.1111/jog.15662

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Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

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Language：Japanese   Publisher：(公社)日本超音波医学会  

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Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2023&ichushi_jid=J03271&link_issn=&doc_id=20230517600024&doc_link_id=10.57291%2Fjsgo.41.2_242&url=https%3A%2F%2Fdoi.org%2F10.57291%2Fjsgo.41.2_242&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

Language：Japanese   Publisher：(公社)日本超音波医学会  

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Language：Japanese   Publisher：(公社)日本超音波医学会  

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Language：Japanese   Publisher：新潟産科婦人科学会  

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Language：English   Publishing type：Research paper (scientific journal)  

TCGA network has clarified that approximately 50% of high-grade serous ovarian cancers show homologous recombination deficiency (HRD). However, the frequency of HRD in Japanese patients with ovarian cancer remains unclear. We aimed to identify the frequency of HR-associated gene mutations in Japanese patients with ovarian cancer. The JGOG3025 study is a multicenter collaborative prospective observational study involving 65 study sites throughout Japan. We recruited 996 patients who were clinically diagnosed with ovarian cancer before surgery from March 2017 to March 2019, and 701 patients were eligible according to the criteria. We used frozen tumor tissues to extract DNA and performed next generation sequencing for 51 targeted genes (including 29 HR-associated genes) in 701 ovarian cancers (298 high-grade serous cases, 189 clear cell cases, 135 endometrioid cases, 12 mucinous cases, 3 low-grade serous cases, and 64 others). HRD was defined as positive when at least one HR-associated gene was mutated. The frequencies of HRD and tumor BRCA1/2 mutations were 45.2% (317/701) and 18.5% (130/701), respectively, in the full analysis set. Next, we performed multivariate Cox proportional hazards regression analysis for progression-free survival (PFS) and overall survival (OS). Advanced-stage ovarian cancer patients with HRD had adjusted hazard ratios of 0.72 (95% CI, 0.55-0.94) and 0.57 (95% CI, 0.38-0.86) for PFS and OS, respectively, compared to those without HRD (p = 0.016 and 0.007). Our study demonstrated that mutations in HR-associated genes were associated with prognosis. Further studies are needed to investigate the prognostic impact of each HR-associated gene in ovarian cancer.

DOI： 10.1111/cas.15747

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Language：Japanese   Publisher：(公社)日本産科婦人科学会  

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Language：Japanese   Publisher：(公社)日本産科婦人科学会  

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Language：Japanese   Publisher：(公社)日本産科婦人科学会  

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Language：Japanese   Publisher：(公社)日本産科婦人科学会  

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Language：Japanese   Publisher：(公社)日本産科婦人科学会  

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Language：Japanese   Publisher：(公社)日本産科婦人科学会  

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Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

DOI： 10.1038/s41416-022-02122-9

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Other Link： https://www.nature.com/articles/s41416-022-02122-9

Publishing type：Research paper (scientific journal)   Publisher：AME Publishing Company  

DOI： 10.21037/atm-23-352

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Language：Japanese   Publisher：東北連合産科婦人科学会・北日本産科婦人科学会  

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Language：Japanese   Publisher：東北連合産科婦人科学会・北日本産科婦人科学会  

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Language：English   Publisher：(一社)日本癌学会  

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Language：Japanese   Publisher：金原出版(株)  

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Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

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Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

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Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

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Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

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Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

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Language：English   Publishing type：Research paper (scientific journal)  

Large-scale data on maternal and neonatal outcomes of pregnancy-associated cervical cancer in Japan are scarce, and treatment strategies have not been established. This multicenter retrospective observational study investigated clinical features and trends in pregnancy-associated cervical cancer treatments at 523 hospitals in Japan. We included cervical cancer cases that were histologically diagnosed (between 1 January 2012, and 31 December 2017), and their clinical information was retrospectively collected. Of 40 patients diagnosed with pregnancy-associated cervical cancer at ≥22 gestational weeks, 34 (85.0%) were carefully followed until delivery without intervention. Of 163 diagnosed at &lt;22 gestational weeks, 111 continued and 52 terminated their pregnancy. Ninety patients with stage IB1 disease had various treatment options, including termination of pregnancy. The 59 stage IB1 patients who continued their pregnancy were categorized by the primary treatment into strict follow-up, conization, trachelectomy, and neoadjuvant chemotherapy groups, with no significant differences in progression-free or overall survival. The birth weight percentile at delivery was smaller in the neoadjuvant chemotherapy group than in the strict follow-up group (p = 0.029). Full-term delivery rate was relatively higher in the trachelectomy group (35%) than in the other groups. Treatment decisions for pregnancy-associated cervical cancer are needed after estimating the stage, considering both maternal and fetal benefits.

DOI： 10.3390/cancers14133072

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Language：English   Publishing type：Research paper (scientific journal)  

Sentinel node navigation surgery (SNNS) is used in clinical practice for the treatment of cervical cancer. This study aimed to elucidate the appropriate sentinel lymph node (SLN) mapping method and assess the safety and benefits of SNNS. We searched the PubMed, Ichushi, and Cochrane Library databases for randomized controlled trials (RCT) and studies on SLN in cervical cancer from January 2012 to December 2020. Two authors independently assessed study quality and extracted data. We quantitatively analyzed the detection rate, sensitivity/specificity, and complications and reviewed information, including the survival data of SLN biopsy (SLNB) without pelvic lymphadenectomy (PLND). The detection rate of SLN mapping in the unilateral pelvis was median 95.7% and 100% and in the bilateral pelvis was median 80.4% and 90% for technetium-99 m (Tc) with/without blue dye (Tc w/wo BD) and indocyanine green (ICG) alone, respectively. The sensitivity and specificity of each tracer were high; the area under the curve of each tracer was 0.988 (Tc w/wo BD), 0.931 (BD w/wo Tc), 0.966 (ICG), and 0.977 (carbon nanoparticle). Morbidities including lymphedema, neurological symptoms and blood loss were associated with PLND. One RCT and five studies all showed SNNS without systematic PLND does not impair recurrence or survival in early-stage cervical cancer with a tumor size ≤ 2-4 cm. Both Tc w/wo BD and ICG are appropriate SLN tracers. SNNS can reduce the morbidities associated with PLND without affecting disease progression in early-stage cervical cancer.

DOI： 10.1007/s10147-022-02178-w

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BACKGROUND: Poly (adenosine diphosphate)-ribose polymerase (PARP) inhibitors for tumors with homologous recombination deficiency (HRD), including pathogenic mutations in BRCA1/2, have been developed. Genomic analysis revealed that about 20% of uterine leiomyosarcoma (uLMS) have HRD, including 7.5%-10% of BRCA1/2 alterations and 4%-6% of carcinomas of the uterine corpus, and 2.5%-4% of the uterine cervix have alterations of BRCA1/2. Preclinical and clinical case reports suggest that PARP inhibitors may be effective against those targets. The Japanese Gynecologic Oncology Group (JGOG) is now planning to conduct a new investigator-initiated clinical trial, JGOG2052. METHODS: JGOG2052 is a single-arm, open-label, multi-center, phase 2 clinical trial to evaluate the efficacy and safety of niraparib monotherapy for a recurrent or persistent rare fraction of gynecologic malignancies with BRCA1/2 mutations except for ovarian cancers. We will independently consider the effect of niraparib for uLMS or other gynecologic malignancies with BRCA1/2 mutations (cohort A, C) and HRD positive uLMS without BRCA1/2 mutations (cohort B). Participants must have 1-3 lines of previous chemotherapy and at least one measurable lesion according to RECIST (v.1.1). Niraparib will be orally administered once a day until lesion exacerbation or unacceptable adverse events occur. Efficacy will be evaluated by imaging through an additional computed tomography scan every 8 weeks. Safety will be measured weekly in cycle 1 and every 4 weeks after cycle 2 by blood tests and physical examinations. The sample size is 16-20 in each of cohort A and B, and 31 in cohort C. Primary endpoint is the objective response rate. TRIAL REGISTRATION: Japan Primary Registries Network (JPRN) Identifier: jRCT2031210264.

DOI： 10.3802/jgo.2022.33.e55

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Language：English   Publishing type：Research paper (scientific journal)  

Ovarian clear cell carcinoma (OCCC) is associated with chemotherapy resistance and poor prognosis, especially in advanced cases. Although comprehensive genomic analyses have clarified the significance of genomic alterations such as ARID1A and PIK3CA mutations in OCCC, therapeutic strategies based on genomic alterations have not been confirmed. On the other hand, OCCC is clinically characterized by a high incidence of thromboembolism. Moreover, OCCC specifically shows high expression of tissue factor and interleukin-6, which play a critical role in cancer-associated hypercoagulation and may be induced by OCCC-specific genetic alterations or the endometriosis-related tumor microenvironment. In this review, we focused on the association between cancer-associated hypercoagulation and molecular biology in OCCC. Moreover, we reviewed the effectiveness of candidate drugs targeting hypercoagulation, such as tissue factor- or interleukin-6-targeting drugs, anti-inflammatory drugs, anti-hypoxia signaling drugs, anticoagulants, and combined immunotherapy with these drugs for OCCC. This review is expected to contribute to novel basic research and clinical trials for the prevention, early detection, and treatment of OCCC focused on hypercoagulation.

DOI： 10.3390/cancers14092125

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1186/s12884-022-04671-6

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Language：Japanese   Publisher：新潟産科婦人科学会  

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Language：Japanese   Publisher：新潟産科婦人科学会  

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Language：Japanese   Publisher：新潟産科婦人科学会  

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Language：Japanese   Publisher：新潟産科婦人科学会  

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It has become evident that somatic mutations in cancer-associated genes accumulate in the normal endometrium, but spatiotemporal understanding of the evolution and expansion of mutant clones is limited. To elucidate the timing and mechanism of the clonal expansion of somatic mutations in cancer-associated genes in the normal endometrium, we sequence 1311 endometrial glands from 37 women. By collecting endometrial glands from different parts of the endometrium, we show that multiple glands with the same somatic mutations occupy substantial areas of the endometrium. We demonstrate that "rhizome structures", in which the basal glands run horizontally along the muscular layer and multiple vertical glands rise from the basal gland, originate from the same ancestral clone. Moreover, mutant clones detected in the vertical glands diversify by acquiring additional mutations. These results suggest that clonal expansions through the rhizome structures are involved in the mechanism by which mutant clones extend their territories. Furthermore, we show clonal expansions and copy neutral loss-of-heterozygosity events occur early in life, suggesting such events can be tolerated many years in the normal endometrium. Our results of the evolutionary dynamics of mutant clones in the human endometrium will lead to a better understanding of the mechanisms of endometrial regeneration during the menstrual cycle and the development of therapies for the prevention and treatment of endometrium-related diseases.

DOI： 10.1038/s41467-022-28568-2

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Neuroendocrine neoplasms of the colon and rectum are colorectal epithelial neoplasms with neuroendocrine differentiation. A platinum regimen used for small cell lung cancer is the currently recommended chemotherapy for gastroenteropancreatic neuroendocrine carcinomas (GEP-NECs), regardless of the organ. The BRAF V600E mutation has been recently reported as a druggable driver mutation in colorectal NECs. In BRAF V600E mutant colorectal cancer, a combination of BRAF inhibitor and anti-epidermal growth factor receptor (EGFR) antibody, with or without a MEK inhibitor, is recommended. Here, we report the case of 77-year-old man who had lymph node recurrence after surgery for primary ascending colonic NEC. Two cytotoxic regimens, cisplatin plus irinotecan and modified FOLFOX6, were administered as first- and second-line chemotherapies with no remarkable response observed. At this point, genetic analysis confirmed the tumor harbored a BRAF V600E mutation. Thus, a regimen of BRAF inhibitor plus anti-EGFR antibody was administered. After commencing this regimen, carcinoembryonic antigen levels decreased within normal range, and there was dramatic shrinkage of the lymph node metastases observed by chest and abdominal computed tomography scans. To our knowledge, this is the first reported case of a colorectal NEC responding to a BRAF inhibitor and anti-EGFR antibody.

DOI： 10.1007/s12328-022-01599-4

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Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

DOI： 10.1038/s10038-021-01003-y

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Other Link： https://www.nature.com/articles/s10038-021-01003-y

Language：Japanese   Publisher：新潟産科婦人科学会  

当院でBevacizumab(Bev)を導入した進行・再発卵巣癌・卵管癌・腹膜癌125例を対象に有害事象について検討を行った。その結果、Grade3以上の有害事象として高血圧16例(12.8%)、蛋白尿5例(4.0%)、血栓塞栓症3例(2.4%)、消化管穿孔2例(1.6%)が認められた。消化管穿孔例はともにGrade4で緊急手術を要し、それぞれ腫瘍と直腸癒着・浸潤部分の穿孔、高度癒着部分の穿孔であった。

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Language：Japanese   Publisher：新潟産科婦人科学会  

当院でBevacizumab(Bev)を導入した進行・再発卵巣癌・卵管癌・腹膜癌125例を対象に有害事象について検討を行った。その結果、Grade3以上の有害事象として高血圧16例(12.8%)、蛋白尿5例(4.0%)、血栓塞栓症3例(2.4%)、消化管穿孔2例(1.6%)が認められた。消化管穿孔例はともにGrade4で緊急手術を要し、それぞれ腫瘍と直腸癒着・浸潤部分の穿孔、高度癒着部分の穿孔であった。

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Uterine leiomyosarcoma (ULMS) is a malignancy, which arises from the uterine smooth muscle. Because of its rarity, aggressive nature, and extremely poor prognosis, the molecular mechanisms driving ULMS remain elusive. To identify candidate cancer genes (CCG) driving ULMS, we conducted an in vivo Sleeping Beauty (SB) transposon mutagenesis screen in uterine myometrium-specific, PTEN knockout, KRAS mutant (PTEN KO/KRAS) mice. ULMS quickly developed in SB PTEN KO/KRAS mice, but not in PTEN KO/KRAS mice, demonstrating the critical importance of SB mutagenesis for driving ULMS in this model. Subsequent sequencing of SB insertion sites in these tumors identified 19 ULMS CCGs that were significantly enriched in known cancer genes. Among them, Zfp217 and Sfmbt2 functioned at early stages of tumor initiation and appeared to be oncogenes. Expression of ZNF217, the human homolog of ZFP217, was shown to be elevated in human ULMS compared with paired normal uterine smooth muscle, where it negatively correlated with patient prognosis. Inhibition of ZNF217 suppressed, whereas overexpression induced, proliferation, survival, migration, and stemness of human ULMS. In a second ex vivo ULMS SB metastasis screen, three CCGs were identified that may drive ULMS metastasis to the lung. One of these CCGs, Nrd1 (NRDC in humans), showed stronger expression in human metastatic tumors compared with primary ULMS and negatively associated with patient survival. NRDC knockdown impaired migration and adhesion without affecting cell proliferation, whereas overexpression had the opposite effect. Together, these results reveal novel mechanism driving ULMS tumorigenesis and metastasis and identify ZNF217 and NRDC as potential targets for ULMS therapy. SIGNIFICANCE: An in vivo Sleeping Beauty transposon mutagenesis screen identifies candidate cancer genes that drive initiation and progression of uterine leiomyosarcoma and may serve as therapeutic targets.

DOI： 10.1158/0008-5472.CAN-21-0356

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Language：Japanese   Publisher：(株)診断と治療社  

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2021&ichushi_jid=J00525&link_issn=&doc_id=20211025050010&doc_link_id=%2Fae4sanke%2F2021%2F008811%2F011%2F1333-1337%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fae4sanke%2F2021%2F008811%2F011%2F1333-1337%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

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Patient-derived cells and xenografts retain the biological characteristics of clinical cancers and are instrumental in gaining a better understanding of the chemoresistance of cancer cells. Here, we have established a panel of patient-derived spheroids from clinical materials of ovarian cancer. Systematic evaluation using therapeutic agents indicated that sensitivity to platinum-based compounds significantly varied among the spheroids. To understand the molecular basis of drug sensitivity, we performed integrative analyses combining chemoresistance data and gene expression profiling of the ovarian cancer patient-derived spheroids. Correlation analyses revealed that cisplatin resistance was significantly associated with elevated levels of glucose-6-phosphate dehydrogenase (G6PD) and glutathione-producing redox enzymes. Accordingly, cisplatin-resistant spheroids established in vitro showed elevated levels of G6PD and active glutathione. Moreover, treatment with a G6PD inhibitor in combination with cisplatin suppressed spheroid proliferation in vitro and largely eradicated peritoneal metastasis in mouse xenograft models. Furthermore, G6PD expression was elevated during carcinogenesis and associated with poor prognosis. Thus, the combination of gene expression data and chemosensitivity revealed the essential roles of G6PD-driven redox metabolism in cisplatin resistance, underscoring the significance of an integrative approach using patient-derived cells.

DOI： 10.1016/j.canlet.2021.08.018

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The histology of the endometrium has traditionally been established by observation of two-dimensional (2D) pathological sections. However, because human endometrial glands exhibit coiling and branching morphology, it is extremely difficult to obtain an entire image of the glands by 2D observation. In recent years, the development of three-dimensional (3D) reconstruction of serial pathological sections by computer and whole-mount imaging technology using tissue clearing methods with high-resolution fluorescence microscopy has enabled us to observe the 3D histoarchitecture of tissues. As a result, 3D imaging has revealed that human endometrial glands form a plexus network in the basalis, similar to the rhizome of grass, whereas mouse uterine glands are single branched tubular glands. This review summarizes the relevant literature on the 3D structure of mouse and human endometrium and discusses the significance of the rhizome structure in the human endometrium and the expected role of understanding the 3D tissue structure in future applications to systems biology.

DOI： 10.3390/jpm11080713

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Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

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Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

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Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

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Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

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Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

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Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

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BACKGROUND: Malignancy during pregnancy is increasing, and the most common type of malignancy is uterine cervical cancer. When planning the treatment of cervical cancer, it is important to look for signs of metastasis before surgery, especially metastasis to the lymph nodes. In this report, we assessed the diagnostic value of positron emission tomography/magnetic resonance imaging (PET/MRI) for evaluating cervical cancer propagation before surgery, with a focus on pregnant women. CASE PRESENTATION: 18F Fluorodeoxyglucose (FDG)-PET/MRI was performed in seven pregnant cervical cancer patients (28-34 years old) at 9-18 gestational weeks. In case #5, a second PET/MRI was performed at 24 gestational weeks. Of seven FDG-PET/MRI examination series in six cases (cases #1-6), FDG-PET/MR imaging could detect cervical tumors with abnormal FDG accumulation; these tumors were confirmed with a standardized uptake value max (SUV max) titer of 4.5-16. A second PET/MRI examination in case #5 revealed the same SUV max titer as the first examination. In these six imaging series (cases #1-5), there were no signs of cancer metastasis to the parametrium and lymph nodes. However, in case #6, abnormal FDG accumulation in the left parametrial lymph nodes was also detectable. Pathological examination showed lymph node metastasis in case #6. In case #7, PET/MRI could not detect any abnormal FDG accumulation in the cervix and other sites. Cone biopsy demonstrated only micro-invasive squamous cell carcinoma. After treatment for cervical cancer, all seven patients have had no recurrence of disease within the follow-up period (2.8-5.6 years), and their children have developed appropriately. CONCLUSION: PET/MRI is an effective imaging tool to evaluate cervical cancer progression in pregnancy.

DOI： 10.1186/s12884-021-03766-w

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BACKGROUND: Mesenteric lymph node (MLN) involvement is often observed in ovarian cancer (OC) with rectosigmoid invasion. This study aimed to investigate the clinical significance of MLN involvement in the pattern of liver metastasis in patients with OC. METHODS: We included 85 stage II-IV OC patients who underwent primary or interval debulking surgery. Twenty-seven patients underwent rectosigmoid resection, whose status of MLN involvement was judged from hematoxylin and eosin (H&E) staining of resected specimens. The prognostic significance of clinicopathological characteristics, including MLN involvement, was evaluated using univariate and multivariate analyses. RESULTS: MLN involvement was detected in 14/85 patients with stage II-IV OC. Residual tumor status, cytology of ascites, and MLN involvement were independent prognostic factors for progression-free survival (PFS; p = 0.033, p = 0.014, and p = 0.008, respectively). When patients were classified into three groups (no MLN, one MLN, two or more MLNs), the number of MLNs involved corresponded to three distinct groups in PFS (p = 0.001). The 3-year cumulative incidence of liver metastasis of patients with MLN involvement was significantly higher than that of patients without MLN involvement (61.1% vs. 8.9%, p < 0.001). MLN involvement was significantly associated with liver metastasis of hematogenous origin (p < 0.001) compared with peritoneal disseminated origin. CONCLUSION: MLN involvement is an important prognostic factor in OC, predicting poor prognosis and liver metastasis of hematogenous origin.

DOI： 10.1245/s10434-021-09899-8

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DOI： 10.1245/s10434-021-09919-7

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Numerous epidemiological and histopathological studies support the notion that clear cell and endometrioid carcinomas derive from ovarian endometriosis. Accordingly, these histologic types are referred to as "endometriosis-associated ovarian cancer" (EAOC). Although the uterine endometrium is also considered an origin of endometriosis, the molecular mechanism involved in transformation of the uterine endometrium to EAOC via ovarian endometriosis has not yet been clarified. Recent studies based on high-throughput sequencing technology have revealed that cancer-associated gene mutations frequently identified in EAOC may exist in the normal uterine endometrial epithelium and ovarian endometriotic epithelium. The continuum of genomic alterations from the uterine endometrium to endometriosis and EAOC has been described, though the significance of cancer-associated gene mutations in the uterine endometrium or endometriosis remains unclear. In this review, we summarize current knowledge regarding the molecular characteristics of the uterine endometrium, endometriosis, and EAOC and discuss the molecular mechanism of cancer development from the normal endometrium through endometriosis in an effort to prevent EAOC.

DOI： 10.3390/cancers13061439

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Language：English   Publishing type：Research paper (scientific journal)  

Advanced-stage gynecologic cancer remains a life-threatening disease. Here, we present a protocol for establishment of stable in vitro 3D spheroid cells derived from human uterine endometrial and ovarian cancer tissues. The tumor-derived spheroid cells have cancer stem cell-related characteristics, including tumorigenesis, and can be used for biological and biochemical analyses and drug efficacy assays. Because these cells possess the biological characteristics of original human tumors, spheroid cells and spheroid-derived xenografts will have applications in personalized medicine in the future. For complete details on the use and execution of this protocol, please refer to Ishiguro et al. (2016) and Mori et al. (2019).

DOI： 10.1016/j.xpro.2021.100354

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Language：Japanese   Publisher：(公社)日本産科婦人科学会  

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Language：Japanese   Publisher：(公社)日本産科婦人科学会  

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Language：Japanese   Publisher：(公社)日本産科婦人科学会  

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Evidence from observational studies indicates that endometriosis and depression often co-occur. However, conflicting evidence exists, and the etiology as well as biological mechanisms underlying their comorbidity remain unknown. Utilizing genome-wide association study (GWAS) data, we comprehensively assessed the relationship between endometriosis and depression. Single nucleotide polymorphism effect concordance analysis (SECA) found a significant genetic overlap between endometriosis and depression (PFsig-permuted = 9.99 × 10-4). Linkage disequilibrium score regression (LDSC) analysis estimated a positive and highly significant genetic correlation between the two traits (rG = 0.27, P = 8.85 × 10-27). A meta-analysis of endometriosis and depression GWAS (sample size = 709,111), identified 20 independent genome-wide significant loci (P < 5 × 10-8), of which eight are novel. Mendelian randomization analysis (MR) suggests a causal effect of depression on endometriosis. Combining gene-based association results across endometriosis and depression GWAS, we identified 22 genes with a genome-wide significant Fisher's combined P value (FCPgene < 2.75 × 10-6). Genes with a nominal gene-based association (Pgene < 0.05) were significantly enriched across endometriosis and depression (Pbinomial-test = 2.90 × 10-4). Also, genes overlapping the two traits at Pgene < 0.1 (Pbinomial-test = 1.31 × 10-5) were significantly enriched for the biological pathways 'cell-cell adhesion', 'inositol phosphate metabolism', 'Hippo-Merlin signaling dysregulation' and 'gastric mucosa abnormality'. These results reveal a shared genetic etiology for endometriosis and depression. Indeed, additional analyses found evidence of a causal association between each of endometriosis and depression and at least one abnormal condition of gastric mucosa. Our study confirms the comorbidity of endometriosis and depression, implicates links with gastric mucosa abnormalities in their causal pathways and reveals potential therapeutic targets for further investigation.

DOI： 10.1007/s00439-020-02223-6

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Language：Japanese   Publisher：(公社)日本産科婦人科学会  

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Language：Japanese   Publisher：(公社)日本産科婦人科学会  

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Language：Japanese   Publisher：(公社)日本産科婦人科学会  

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Language：Japanese   Publisher：新潟産科婦人科学会  

症例1は80歳で、約2年前から子宮下垂感を自覚し、約1年前から排便時に直腸脱を認めるようになった。今回、Stage IVの子宮脱および完全直腸脱の診断で一期的根治手術を行う方針となり、腹腔鏡下にWells直腸後方固定術+子宮腟上部切断+両側付属器切除+シングルメッシュによる仙骨腟固定術を施行し、術後経過良好であった。症例2は78歳で、約2年前から子宮脱を自覚し、間欠的自己還納で対応していた。半年前に排尿困難感が出現し、手術目的で当科を紹介受診した。初回受診時は子宮脱のみであったが、2回目の診察で直腸脱の併発を認めた。今回、Stage IVの子宮脱および完全直腸脱の診断で症例1と同様の手術を行い、術後経過良好であった。

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Language：Japanese   Publisher：新潟産科婦人科学会  

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Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

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Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

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Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

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Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

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Language：Japanese   Publisher：新潟産科婦人科学会  

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Language：Japanese   Publisher：新潟産科婦人科学会  

セプラフィルムは優れた癒着防止効果が報告されているが、腹腔鏡下手術での体腔内搬入や貼付操作に難渋することが多い。今回、セプラフィルムの操作にEndoロールを用いた方法を試行し、その有効性について従来法(リデューサーを用いる方法)と比較検討した。腹腔鏡下単純子宮全摘出術3例にEndoロールを使用した結果、3例とも充填が比較的簡便に途中で破損することなく可能であった。最も優れていた点は、5mmポートから挿入可能なため、カメラで確認しながら安全に体腔内搬入でき、周囲臓器にセプラフィルムが付着する前に、広がったままの状態で受け取ることにより貼付が容易な点であった。

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BACKGROUND: Mounting evidence for the role of distal fallopian tubes in the pathogenesis of epithelial ovarian cancer has led to opportunistic salpingectomy being increasingly performed at the time of benign gynecologic surgery. Opportunistic salpingectomy has now been recommended as best practice in the United States to reduce future risk of ovarian cancer even in low-risk women. Preliminary analyses have suggested that performance of opportunistic salpingectomy is increasing. OBJECTIVE: To examine trends in opportunistic salpingectomy in women undergoing benign hysterectomy and to determine how the publication of the tubal hypothesis in 2010 may have contributed to these trends. STUDY DESIGN: This is a population-based, retrospective, observational study examining the National Inpatient Sample between January 2001 and September 2015. Women younger than 50 years who underwent inpatient hysterectomy for benign gynecologic disease were grouped as hysterectomy alone vs hysterectomy with opportunistic salpingectomy. All women had ovarian conservation, and those with adnexal pathology were excluded. Linear segmented regression with log transformation was used to assess temporal trends. An interrupted time-series analysis was then used to assess the impact of the 2010 publication of the tubal hypothesis on opportunistic salpingectomy trends. A regression-tree model was constructed to examine patterns in the use of opportunistic salpingectomy. A binary logistic regression model was then fitted to identify independent characteristics associated with opportunistic salpingectomy. Sensitivity analysis was performed in women aged 50-65 years to further assess surgical trends in a wider age group. RESULTS: There were 98,061 (9.0%) women who underwent hysterectomy with opportunistic salpingectomy and 997,237 (91.0%) women who underwent hysterectomy alone without opportunistic salpingectomy. The rate at which opportunistic salpingectomy was being performed gradually increased from 2.4% to 5.7% between 2001 and 2010 (2.4-fold increase; P<.001), predicting a 7.0% rate of opportunistic salpingectomy in 2015. However, in 2010, the rate of opportunistic salpingectomy began to increase substantially and reached 58.4% by 2015 (10.2-fold increase; P<.001). In multivariable analysis, the largest change in the performance of opportunistic salpingectomy occurred after 2010 (adjusted odds ratio, 5.42; 95% confidence interval, 5.34-5.51; P<.001). In a regression-tree model, women who had a hysterectomy at urban teaching hospitals in the Midwest after 2013 had the highest chance of undergoing opportunistic salpingectomy during benign hysterectomy (76.4%). In the sensitivity analysis of women aged 50-65 years, a similar exponential increase in opportunistic salpingectomy was observed from 5.8% in 2010 to 55.8% in 2015 (9.8-fold increase; P<.001). CONCLUSION: Our study suggests that clinicians in the United States rapidly adopted opportunistic salpingectomy at the time of benign hysterectomy following the publication of data implicating the distal fallopian tubes in ovarian cancer pathogenesis in 2010. By 2015, nearly 60% of women had undergone opportunistic salpingectomy at benign hysterectomy.

DOI： 10.1016/j.ajog.2020.04.028

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Language：Japanese   Publisher：(一社)日本産科婦人科内視鏡学会  

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Language：Japanese   Publisher：(一社)日本産科婦人科内視鏡学会  

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Language：Japanese   Publisher：(一社)日本産科婦人科内視鏡学会  

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Language：Japanese   Publisher：(一社)日本産科婦人科内視鏡学会  

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Language：Japanese   Publisher：(一社)日本産科婦人科内視鏡学会  

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Language：Japanese   Publisher：(一社)日本産科婦人科内視鏡学会  

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Language：Japanese   Publisher：(一社)日本産科婦人科内視鏡学会  

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Language：English   Publisher：(一社)日本癌学会  

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Whether germline (g) breast cancer susceptibility gene (BRCA) mutations are located within or outside the ovarian cancer cluster region (OCCR) (1380-4062 bp for gBRCA1, and between 3249-5681 bp and 6645-7471 bp for gBRCA2) may influence risk variations for ovarian cancers. This ad hoc analysis of the CHARLOTTE epidemiological study in Japan assessed the distribution of gBRCA1/2 mutations in patients with newly diagnosed ovarian cancer, and investigated an association between gBRCA1/2 mutation locations and ovarian cancer risk. Differences in patient background and clinical characteristics in subgroups stratified by gBRCA1/2 mutation locations were also evaluated. We analyzed the data of 93 patients (14.7%) from the CHARLOTTE study who were positive for gBRCA1/2 mutations. After excluding 16 cases with L63X founder mutation, 28 (65.1%) of gBRCA1 mutations were within the OCCR. Of 30 gBRCA2 mutations, 15 (50.0%) were within the OCCR. Of 27 patients (one patient excluded for unknown family history) with gBRCA1 mutations located in the OCCR, 11 (40.7%) had a family history of ovarian cancer; the proportion of patients with a family history of ovarian cancer and gBRCA1 mutations outside the OCCR was lower (13.3%). Sixty percent of patients with gBRCA1 mutations outside the OCCR had a family history of breast cancer; the proportion of patients with a family history of breast cancer and gBRCA1 mutations within the OCCR was relatively lower (33.3%). Understanding the mutation locations may contribute to more accurate risk assessments of susceptible individuals and early detection of ovarian cancer among gBRCA mutation carriers.

DOI： 10.1111/cas.14513

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ARID1A loss-of-function mutation accompanied by a loss of ARID1A protein expression is considered one of the most important driver events in endometriosis-associated ovarian cancer. Although our recent genomic study clarified that ARID1A loss-of-function mutations were detected in 13% of ovarian endometriosis, an association between the ARID1A mutation status and ARID1A protein expression in ovarian endometriosis remains unclear. We performed immunohistochemical staining for ARID1A in 78 ovarian endometriosis samples and 99 clear cell carcinoma samples. We revealed that not only 70 endometriosis samples without ARID1A mutations but also eight endometriosis samples with ARID1A loss-of-function mutations retained ARID1A protein expression. On the other hand, most of clear cell carcinomas with ARID1A loss-of-function mutations showed a loss of ARID1A protein expression. In particular, clear cell carcinoma samples which harbor multiple ARID1A loss-of-function mutations or both a single ARID1A loss-of-function mutation and ARID1A allelic imbalance lost ARID1A protein expression. However, ARID1A protein expression was retained in seven clear cell carcinomas with ARID1A loss-of-function mutations. These results suggest that a single ARID1A loss-of-function mutation is insufficient for ARID1A loss in ovarian endometriosis and some clear cell carcinoma. Further driver events may be needed for the malignant transformation of ovarian endometriosis with ARID1A loss-of-function mutations.

DOI： 10.1038/s41598-020-71273-7

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Language：English   Publishing type：Research paper (scientific journal)  

PURPOSE: To examine trends, characteristics and outcomes of women who develop both ovarian and breast cancers. METHODS: This is a retrospective study examining the Surveillance, Epidemiology, and End Results Program from 1973 to 2013. Among ovarian cancer (n = 133,149) and breast cancer (n = 1,143,219) cohorts, women with both diagnoses were identified and temporal trends, tumor characteristics and survival were examined. RESULTS: There were 6446 women with both malignancies, representing 4.8% of the ovarian cancer cohort and 0.6% of the breast cancer cohort. Women with ovarian cancer who had secondary breast cancer were younger than those without secondary breast cancer early in the study period (52.3 versus 59.2 in 1973) but older in more recent years (68.5 versus 62.1 in 2013, P < 0.001). The number of breast cancer survivors who developed postcedent ovarian cancer decreased from 1.5 to 0.2% from 1979 to 2008 (relative risk reduction 90.0%, P < 0.05). Similarly, the number of ovarian cancer survivors who developed postcedent breast cancer decreased from 7.2 to 2.0% from 1973 to 2008 (relative risk reduction 72.4%, P < 0.05). Tumor characteristics were more likely to be favorable in women with ovarian cancer who developed postcedent breast cancer but unfavorable in those who had antecedent breast cancer (all, P < 0.05). Women with ovarian cancer who had secondary breast cancer had superior cause-specific survival compared to those who did not develop breast cancer regardless of breast cancer timing (P < 0.05). CONCLUSION: Our study demonstrated that the demographics of women who develop breast cancer and ovarian cancer have changed over time and diagnosis of secondary breast cancer after ovarian cancer has decreased.

DOI： 10.1007/s00404-020-05508-3

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Language：Japanese   Publisher：(公社)日本産科婦人科学会  

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Observational epidemiological studies indicate that endometriosis and migraine co-occur within individuals more than expected by chance. However, the aetiology and biological mechanisms underlying their comorbidity remain unknown. Here we examined the relationship between endometriosis and migraine using genome-wide association study (GWAS) data. Single nucleotide polymorphism (SNP) effect concordance analysis found a significant concordance of SNP risk effects across endometriosis and migraine GWAS. Linkage disequilibrium score regression analysis found a positive and highly significant genetic correlation (rG = 0.38, P = 2.30 × 10-25) between endometriosis and migraine. A meta-analysis of endometriosis and migraine GWAS data did not reveal novel genome-wide significant SNPs, and Mendelian randomisation analysis found no evidence for a causal relationship between the two traits. However, gene-based analyses identified two novel loci for migraine. Also, we found significant enrichment of genes nominally associated (Pgene < 0.05) with both traits (Pbinomial-test = 9.83 × 10-6). Combining gene-based p-values across endometriosis and migraine, three genes, two (TRIM32 and SLC35G6) of which are at novel loci, were genome-wide significant. Genes having Pgene < 0.1 for both endometriosis and migraine (Pbinomial-test = 1.85 ×10-°3) were significantly enriched for biological pathways, including interleukin-1 receptor binding, focal adhesion-PI3K-Akt-mTOR-signaling, MAPK and TNF-α signalling. Our findings further confirm the comorbidity of endometriosis and migraine and indicate a non-causal relationship between the two traits, with shared genetically-controlled biological mechanisms underlying the co-occurrence of the two disorders.

DOI： 10.3390/genes11030268

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Nature  

DOI： 10.1038/s41416-019-0654-8

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Publishing type：Research paper (scientific journal)   Publisher：Asian Society of Gynecologic Oncology; Korean Society of Gynecologic Oncology and Colposcopy  

DOI： 10.3802/jgo.2019.30.e114

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Other Link： https://synapse.koreamed.org/DOIx.php?id=10.3802/jgo.2019.30.e114

Language：Japanese   Publisher：新潟県臨床細胞学会  

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Language：English   Publisher：(一社)日本癌治療学会  

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Uterine endometrial cancer is associated with poor survival outcomes in patients with advanced-stage disease. Here, we developed a three-dimensional cell cultivation method of endometrioid cancer stem-like cells with high aldehyde dehydrogenase (ALDH) activity from clinical specimens. ALDH inhibition synergized with paclitaxel to block cancer proliferation. In the clinical setting, high ALDH1A1 expression was associated with poor survival. A high level of ALDH correlated with an increase of glucose uptake, activation of the glycolytic pathway, and elevation of glucose transporter 1 (GLUT1). Blockade of GLUT1 inhibited characteristics of cancer stem cells. Similarly to ALDH inhibition, GLUT1 inhibition synergized with paclitaxel to block endometrial cancer proliferation. Our data indicated that ALDH-dependent GLUT1 activation and the resulting glycolytic activation are of clinical importance for both prognostic evaluation and therapeutic decision-making in endometrial cancer patients. In addition, the synergistic effects of taxane compounds and ALDH or GLUT1 inhibitors may serve as a new clinical treatment option for endometrial cancer.

DOI： 10.1016/j.stemcr.2019.08.015

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Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.ygyno.2019.08.007

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Language：Japanese   Publisher：(一社)日本女性医学学会  

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Language：English   Publisher：(一社)日本癌治療学会  

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Language：Japanese   Publisher：(一社)日本産科婦人科内視鏡学会  

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Language：Japanese   Publisher：(一社)日本産科婦人科内視鏡学会  

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Language：Japanese   Publisher：(一社)日本産科婦人科内視鏡学会  

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Language：Japanese   Publisher：(一社)日本産科婦人科内視鏡学会  

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DOI： 10.1016/j.ygyno.2019.05.014

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Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

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Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

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DOI： 10.3390/jcm8050714

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Retroperitoneal high-grade serous carcinoma (HGSC) is extremely rare and the origin remains unclear. We present a case of retroperitoneal HGSC and coexisting serous tubal intraepithelial carcinoma (STIC), which is considered as the main origin of ovarian HGSC. We reviewed the available literature and discussed about the origin of this rare disease. CASE PRESENTATION: A 58-year-old female with a 93 × 65 × 62 mm-solid tumor with a cystic part was located immediately dorsal to the rectum underwent bilateral salpingo-oophorectomy, total abdominal hysterectomy, and en bloc resection of the retroperitoneal tumor together with lower anterior resection of the rectum. Histological diagnosis was retroperitoneal HGSC and STIC at the right fallopian tube. Two deleterious somatic mutations in TP53 and BRCA2 genes were shared between retroperitoneal HGSC and STIC. CONCLUSIONS: In addition to clinical features in the previous reports, our genetic findings suggest the origin of retroperitoneal HGSC might be STIC.

DOI： 10.1186/s13000-019-0795-3

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Language：Japanese   Publisher：(公社)日本産科婦人科学会  

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Language：Japanese   Publisher：新潟産科婦人科学会  

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Language：Japanese   Publisher：(公社)日本産科婦人科学会  

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Language：Japanese   Publisher：新潟産科婦人科学会  

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Language：English   Publishing type：Research paper (scientific journal)  

We explored the frequency of germline and somatic mutations in homologous recombination (HR)-associated genes in major histological types of ovarian cancer. We performed targeted sequencing to assess germline and somatic mutations of 16 HR-associated genes and 4 mismatch repair (MMR) genes among 207 ovarian cancer patients (50 high-grade serous carcinomas (HGSC), 99 clear cell carcinomas (CCC), 39 endometrioid carcinomas (EC), 13 mucinous carcinomas (MC), and 6 low-grade serous carcinomas (LGSC)). Germline or somatic mutations of HR-associated genes were detected in 44% of HGSC, 28% of CCC, 23% of EC, 16% of MC, and 17% of LGSC patients. The profile of HR-associated gene mutations was remarkably different among each histological type. Germline BRCA1/2 mutations were frequently detected in HGSC and were rarely observed in CCC, EC, and MC patients. ATM somatic mutation was more frequently detected in CCC (9%) and EC patients (18%) than in HGSC patients (4%). There was a positive correlation between MMR gene mutations and HR-associated gene mutations (p = 0.0072). Our findings might be useful in selection of ovarian cancer patients that should be treated with PARP inhibitors.

DOI： 10.1038/s41598-019-54116-y

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Language：English   Publishing type：Research paper (scientific journal)  

Primary ovarian sarcomas are extremely rare tumors, and their genomic and transcriptomic alterations remain to be elucidated. We performed whole exome sequencing of primary tumor and matched normal blood samples derived from one patient with ovarian undifferentiated small round cell sarcoma. We identified 8 nonsynonymous somatic mutations, and all mutations were missense or nonsense changes. Next, we performed RNA sequencing of the tumor sample and identified two in-frame fusion transcripts: MXD4-NUTM1 and ARL6-POT1. Most NUTM1 exons were retained in the MXD4-NUTM1 fusion transcript, and we confirmed an increase in NUTM1 mRNA and protein expression in tumor tissue. Further genomic and transcriptomic analyses might lead to the development of new therapeutic strategies based on the molecular characteristics of ovarian undifferentiated small round cell sarcoma.

DOI： 10.1002/gcc.22668

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Language：Japanese   Publisher：新潟産科婦人科学会  

腹腔鏡下子宮全摘術(TLH)を施行した既往帝王切開31例を対象とし、定型化した帝王切開術後の膀胱剥離法を開始前の3例(42〜51歳)と開始後28例(41〜62歳)であった。手術適応では、開始後で子宮体癌の症例数が11例と多かった。開腹への移行、膀胱損傷など、手技に関係する術中・術後の合併症は認めなかった。入院期間、手術時間に顕著な差は認めなかったが、出血量は開始後で少ない傾向にあった。

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Language：Japanese   Publisher：(公社)日本人間ドック学会  

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Language：Japanese   Publisher：(一社)日本産科婦人科内視鏡学会  

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Language：Japanese   Publisher：(一社)日本産科婦人科内視鏡学会  

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Language：Japanese   Publisher：(株)メジカルビュー社  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Lippincott Williams and Wilkins  

DOI： 10.1097/IGC.0000000000001218

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Other Link： http://orcid.org/0000-0002-2254-3378

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Nature Publishing Group  

DOI： 10.1038/s41388-017-0033-y

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Other Link： http://orcid.org/0000-0002-2254-3378

Language：Japanese   Publisher：北海道産科婦人科学会  

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Language：Japanese   Publisher：北海道産科婦人科学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Blackwell Publishing  

DOI： 10.1111/jog.13472

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Other Link： http://orcid.org/0000-0002-2254-3378

Language：Japanese   Publisher：新潟産科婦人科学会  

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Language：English   Publisher：(一社)日本癌学会  

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Language：Japanese   Publisher：東北連合産科婦人科学会・北日本産科婦人科学会  

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1073/pnas.1705441114

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Other Link： http://orcid.org/0000-0002-2254-3378

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1038/bjc.2017.228

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Other Link： http://orcid.org/0000-0002-2254-3378

Language：Japanese   Publisher：新潟産科婦人科学会  

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Language：Japanese   Publisher：(一社)日本産科婦人科内視鏡学会  

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Language：Japanese   Publisher：新潟産科婦人科学会  

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Language：Japanese   Publisher：(一社)日本産科婦人科内視鏡学会  

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Language：Japanese   Publisher：(一社)日本産科婦人科内視鏡学会  

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Language：Japanese   Publisher：(一社)日本産科婦人科内視鏡学会  

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Language：Japanese   Publisher：新潟産科婦人科学会  

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Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

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Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

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Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1038/ncomms15539

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Other Link： http://orcid.org/0000-0002-2254-3378

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1111/cas.13196

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Language：Japanese   Publisher：(公社)日本産科婦人科学会  

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Language：English  

DOI： 10.1172/JCI91191

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Other Link： http://orcid.org/0000-0002-2254-3378

Language：Japanese   Publisher：(一社)日本癌治療学会  

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Language：Japanese   Publisher：(一社)日本癌治療学会  

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Language：Japanese   Publisher：東北連合産科婦人科学会・北日本産科婦人科学会  

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Language：Japanese   Publisher：東北連合産科婦人科学会・北日本産科婦人科学会  

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1053/j.gastro.2016.04.040

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Other Link： http://orcid.org/0000-0002-2254-3378

Language：Japanese   Publisher：(一社)日本産科婦人科内視鏡学会  

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Language：Japanese   Publisher：(一社)日本産科婦人科内視鏡学会  

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Language：Japanese   Publisher：(一社)日本産科婦人科内視鏡学会  

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Language：Japanese   Publisher：(一社)日本産科婦人科内視鏡学会  

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Language：Japanese   Publisher：(一社)日本産科婦人科内視鏡学会  

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1097/AOG.0000000000001491

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Language：Japanese   Publisher：新潟産科婦人科学会  

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Language：Japanese   Publisher：新潟産科婦人科学会  

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Language：Japanese   Publisher：新潟産科婦人科学会  

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1073/pnas.1606876113

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Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

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Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

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Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

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Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

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Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.ajpath.2015.12.029

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Other Link： http://orcid.org/0000-0002-2254-3378

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1371/journal.pgen.1005893

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1038/bjc.2016.27

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Other Link： http://orcid.org/0000-0002-2254-3378

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1111/jog.12877

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Other Link： http://orcid.org/0000-0002-2254-3378

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1038/srep18657

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Language：Japanese   Publisher：新潟産科婦人科学会  

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Language：Japanese   Publisher：新潟産科婦人科学会  

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Language：Japanese   Publisher：東北連合産科婦人科学会・北日本産科婦人科学会  

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Language：Japanese   Publisher：(一社)日本産科婦人科内視鏡学会  

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Language：Japanese   Publisher：(一社)日本産科婦人科内視鏡学会  

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Language：Japanese   Publisher：新潟産科婦人科学会  

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Language：Japanese   Publisher：(一社)日本産科婦人科内視鏡学会  

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Language：Japanese   Publisher：(一社)日本産科婦人科内視鏡学会  

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Language：Japanese   Publisher：新潟産科婦人科学会  

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1007/s10815-015-0468-4

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Other Link： http://orcid.org/0000-0002-2254-3378

Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

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Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1038/onc.2014.216

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1371/journal.pone.0116977

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Other Link： http://orcid.org/0000-0002-2254-3378

Language：Japanese   Publisher：新潟県医師会  

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Mobile elements comprise about half of the human genome. Three active mobile element families (L1, Alu, and SVA) possibly cause diseases such as cancer. We conducted mobile element insertion (MEI) profiling of 44 epithelial ovarian cancers using exome-sequencing data. We identified a total of 106 MEIs using the Mobster program, 8 of which were novel exonic MEIs.

DOI： 10.1038/hgv.2015.30

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.4172/2157-7420.1000180

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BioMed Central Ltd.  

DOI： 10.1186/s13059-014-0563-3

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1038/ncomms4887

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1007/s10147-013-0530-0

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High-grade serous ovarian cancer (HGSOC) is the most aggressive histological type of epithelial ovarian cancer, which is characterized by a high frequency of somatic TP53 mutations. We performed exome analyses of tumors and matched normal tissues of 34 Japanese patients with HGSOC and observed a substantial number of patients without TP53 mutation (24%, 8/34). Combined with the results of copy number variation analyses, we subdivided the 34 patients with HGSOC into subtypes designated ST1 and ST2. ST1 showed intact p53 pathway and was characterized by fewer somatic mutations and copy number alterations. In contrast, the p53 pathway was impaired in ST2, which is characterized by abundant somatic mutations and copy number alterations. Gene expression profiles combined with analyses using the Gene Ontology resource indicate the involvement of specific biological processes (mitosis and DNA helicase) that are relevant to genomic stability and cancer etiology. In particular we demonstrate the presence of a novel subtype of patients with HGSOC that is characterized by an intact p53 pathway, with limited genomic alterations and specific gene expression profiles.

DOI： 10.1371/journal.pone.0114491

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DOI： 10.1172/JCI74035

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DOI： 10.1038/ng.2764

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1172/JCI68509

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Language：English   Publisher：Nature Publishing Group  

Our previous genome-wide association study has demonstrated that single-nucleotide polymorphisms (SNPs) located in intronic and downstream regions of IL1A (interleukin 1α) were associated with the risk of endometriosis. These SNPs on the genome-wide association study platform could be only surrogates for the true causal variant. Thus, we resequenced all the exons of IL1A in 377 patients with endometriosis and 457 healthy controls. We detected seven rare variants (minor allele frequency <0.01) and four common variants. All the rare variants were not associated with endometriosis. The four common variants (rs17561, rs1304037, rs2856836 and rs3783553) in IL1A were significantly associated with endometriosis (P=0.0024, 0.0024, 0.0014 and 0.0061, respectively). All the four SNPs were within a linkage disequilibrium block. Among them, only rs17561 was nonsynonymous (p.A114S), which has been reported to be associated with susceptibility to ovarian cancer. Taken together, we examined association between rs17561 and endometriosis in an independent validation data set (524 patients and 533 healthy controls) replicating significant association (P=4.0 × 10(-5); odds ratio (OR), 1.91; 95% confidence interval (CI), 1.41-2.61). Meta-analysis by combining results from the two stages strengthened the evidence of association (P=2.5 × 10(-7); OR, 1.90; 95% CI, 1.49-2.43). Our findings demonstrated that the nonsynonymous variant of IL1A might confer genetic susceptibility to endometriosis in Japanese population.

DOI： 10.1038/jhg.2013.32

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wiley Blackwell (Blackwell Publishing)  

DOI： 10.1111/j.1447-0756.2012.01961.x

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Sekine M, Yoshihara K, Tanaka K, &lt;i&gt;Nihon rinsho. Japanese journal of clinical medicine&lt;/i&gt;, 2012, vol. 70 Suppl 4, pp. 469-474

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DOI： 10.1093/humrep/des080

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Language：Japanese   Publisher：(株)日本臨床社  

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Language：Japanese   Publisher：Japanese Journal of Cancer and Chemotherapy Publishers Inc.  

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1002/gcc.20841

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.3390/ijms12020971

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DOI： 10.1159/000330202

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DOI： 10.1038/jhg.2010.118

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DOI： 10.1016/j.ygyno.2010.07.007

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DOI： 10.1371/journal.pone.0009615

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1111/j.1349-7006.2009.01204.x

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Language：Japanese   Publisher：(株)診断と治療社  

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Language：Japanese   Publisher：(株)メディカルレビュー社  

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2021&ichushi_jid=J02833&link_issn=&doc_id=20210608160006&doc_link_id=10.34449%2FJ0015.28.02_0027-0030&url=https%3A%2F%2Fdoi.org%2F10.34449%2FJ0015.28.02_0027-0030&type=%88%E3%8F%91.jp_%83I%81%5B%83%8B%83A%83N%83Z%83X&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00024_2.gif

Language：Japanese   Publisher：金原出版(株)  

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Language：English   Publishing type：Research paper, summary (international conference)  

Web of Science

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J-GLOBAL

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J-GLOBAL

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Language：Japanese   Publisher：(株)メディカルレビュー社  

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Language：Japanese   Publisher：日本エンドメトリオーシス学会  

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Language：Japanese   Publisher：日本婦人科病理学会  

卵巣癌は、The Cancer Genome Atlasの第1期に解析対象になった疾患で、オミックス解析が進んでいる癌種の一つである。本稿では、これまでに報告されている卵巣癌ゲノム解析の結果を、1)高異型度漿液性癌、2)粘液性癌、3)内膜症関連卵巣癌、の各項目で整理した。さらに、当科で取り組んでいる「正常子宮内膜のゲノム異常に注目した子宮内膜症・内膜症関連卵巣癌の病態解明」研究の成果を報告した。ゲノム解析のため、卵巣子宮内膜症13症例から子宮内膜症上皮、また子宮摘出が行われた卵巣子宮内膜症5症例と内膜症以外の婦人科良性疾患症例から正常子宮内膜上皮を採取し、DNAを抽出して全エクソンシークエンスを行った。その結果、内膜症上皮と子宮内膜上皮ともに遺伝子を多数認めた。また、癌関連遺伝子(KRAS、PIK3CA、FBXW7、ARHGAP35、PPP2R1A、PIK3R1、PTPN13)変異は内膜症上皮だけでなく子宮内膜上皮にも存在することが明らかになった。KRASおよびPIK3CAの変異アリル頻度は子宮内膜上皮に比して内膜症上皮で有意に高く、KRAS変異やPIK3CA変異を持つ内膜症上皮細胞がクローン性に増殖していることが示唆された。

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Language：Japanese   Publisher：(公財)上原記念生命科学財団  

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Language：Japanese   Publisher：(公社)日本産科婦人科学会  

著者らは「オミックスデータ解析から婦人科悪性腫瘍の発生を探る」をテーマに掲げ、日本人に多いとされる内膜症関連卵巣癌のゲノム解析を行った。その結果、これまで内膜症関連卵巣癌で指摘されていた遺伝子変異であるPIK3CAやKRASはすでに子宮内膜上皮や卵巣子宮内膜症上皮に存在することが明らかとなった。子宮内膜上皮が癌関連遺伝子変異を有することで、月経血逆流による異所への移動・生着および増殖に有利に働き、子宮内膜症の発症につながると考えられた。そして、癌関連遺伝子変異を有する内膜症上皮に、ドライバー遺伝子の異常が加わることで癌が発生すると推察された。

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Language：Japanese   Publisher：(一社)日本産科婦人科内視鏡学会  

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Language：Japanese   Publisher：(一社)日本産科婦人科内視鏡学会  

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Language：Japanese   Publisher：(公社)日本人間ドック学会  

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Language：Japanese   Publisher：(公社)日本産科婦人科学会  

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Language：English   Publishing type：Research paper, summary (international conference)  

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Language：English   Publisher：日本癌学会  

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Language：Japanese   Publisher：(一社)日本産科婦人科内視鏡学会  

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Language：Japanese   Publisher：(一社)日本産科婦人科内視鏡学会  

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Language：Japanese   Publisher：(一社)日本産科婦人科内視鏡学会  

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Language：Japanese   Publisher：(一社)日本産科婦人科内視鏡学会  

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Language：English   Publishing type：Research paper, summary (international conference)  

DOI： 10.1158/1538-7445.AM2017-529

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Language：English   Publishing type：Research paper, summary (international conference)  

DOI： 10.1158/1538-7445.AM2017-411

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Language：Japanese   Publisher：新潟医学会  

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Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

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Language：Japanese   Publisher：(株)最新医学社  

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Other Link： http://search.jamas.or.jp/link/ui/2017201267

Language：Japanese   Publisher：新潟産科婦人科学会  

婦人科悪性腫瘍手術の周術期予防的抗菌薬投与について検討した。開腹による悪性腫瘍根治術を施行し、術後の抗生剤を使用せず周術期のみセファゾリン(CEZ)を使用した140例を対象とした。手術部位感染(SSI)を発症した感染例6例、非感染例134例であった。6例でSSIを認めたが、6時間以上の手術20例では3例でSSIを発症した。術後1日目のCRP値は、感染群で高値の傾向があった。発症率は、腸管切除施行83%、施行していない32%であったが、有意差を認めなかった。抗菌剤投与が適正に行われていた60例中1例、適正投与されなかった44例中3例でSSIを発症していたが、有意差は認めなかった。腸管切除を施行した12例のうち8例に3時間毎の適正な抗菌剤投与が施行された。

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Other Link： http://search.jamas.or.jp/link/ui/2016398677

Language：Japanese   Publisher：日本産科婦人科学会  

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Other Link： https://projects.repo.nii.ac.jp/?action=repository_uri&item_id=456622

Language：Japanese   Publisher：日本産科婦人科学会  

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Other Link： https://projects.repo.nii.ac.jp/?action=repository_uri&item_id=456638

Language：Japanese   Publisher：新潟産科婦人科学会 ; 2011-  

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Language：Japanese   Publisher：日本産科婦人科学会  

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Other Link： https://projects.repo.nii.ac.jp/?action=repository_uri&item_id=454037

Language：English  

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Other Link： https://projects.repo.nii.ac.jp/?action=repository_uri&item_id=455399

Language：Japanese   Publisher：日本産科婦人科学会  

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Other Link： https://projects.repo.nii.ac.jp/?action=repository_uri&item_id=454407

Language：Japanese   Publisher：日本産科婦人科学会  

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Other Link： https://projects.repo.nii.ac.jp/?action=repository_uri&item_id=454895

Language：Japanese   Publisher：日本産科婦人科学会  

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Other Link： https://projects.repo.nii.ac.jp/?action=repository_uri&item_id=453999

Language：Japanese   Publisher：日本産科婦人科学会  

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Other Link： https://projects.repo.nii.ac.jp/?action=repository_uri&item_id=453873

Language：English   Publishing type：Research paper, summary (international conference)  

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Language：Japanese   Publisher：(株)診断と治療社  

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Other Link： http://search.jamas.or.jp/link/ui/2014229547

Language：Japanese   Publisher：(一社)日本癌治療学会  

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Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

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Language：Japanese   Publisher：日本産科婦人科学会  

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Other Link： https://projects.repo.nii.ac.jp/?action=repository_uri&item_id=453287

Language：English   Publisher：日本癌学会  

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Language：Japanese   Publisher：日本エンドメトリオーシス学会  

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Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

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Language：Japanese   Publisher：(株)癌と化学療法社  

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Other Link： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2012&ichushi_jid=J00296&link_issn=&doc_id=20120507460004&doc_link_id=%2Fab8gtkrc%2F2012%2F003904%2F004%2F0506-0511%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fab8gtkrc%2F2012%2F003904%2F004%2F0506-0511%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif